Novel enolamides, pharmaceutical compositions and methods of use thereof for activity as modulators of the arachidonic acid cascade

ABSTRACT

The present invention relates to novel enolamide type compounds, pharmaceutical compositions, and methods of use thereof, useful in the treatment of diseases in which products of lipoxygenase enzyme activity or the action of leukotrienes contribute to the pathological condition.

This application is a divisional of U.S. Ser. No. 121,264 filed Nov. 16,1987, which is a divisional of U.S. Ser. No. 782,623 filed Oct. 1, 1985,now U.S. Pat. No. 4,761,424.

BACKGROUND OF THE INVENTION

The present invention relates to novel compounds, pharmaceuticalcompositions, and methods of use for the treatment of diseases in whichproducts of lipoxygenase enzyme activity or the action of leukotrienescontribute to the pathological condition. The novel compounds of thepresent invention have activity useful for treating asthma, allergies,cardiovascular diseases, migraines, and immunoinflammatory conditions.Selected novel intermediates are also the present invention.

More particularly, this invention concerns certain novel enolamideshaving the Formula I as defined below, pharmaceutical compositionshaving the novel enolamides therein, and methods of use therefor in thetreatment or amelioration of diseases in which products of lipoxygenaseenzyme activity or the reaction of leukotrienes contribute to thepathological condition. That is, the novel enolamides inhibitlipoxygenase and/or bind leukotriene receptors. Lipoxygenase enzymes arewell known in the arachidonic acid cascade.

Arachidonic acid serves as the biological precursor for a family ofphysiologically active eicosanoids. These include products derived fromthe action of cyclooxygenase such as the class of prostaglandin-E and -Fcompounds, thromboxanes, and prostacyclin, and products derived from theaction of lipoxygenase enzymes such as hydroxy- andhydroperoxyeicosatetraenoic acids and the leukotrienes.

Lipoxygenase pathway products such as leukotrienes B4, C4, D4, and E4,5-hydroxyeicosatetraenoic acid, 5-hydroperoxyeicosatetraenoic acid, and12-hydroxyeicosatetraenoic acid are related to the condition recognizedas inflammation, and in allergic and immune responses.

These lipoxygenase products have been shown to be highly potentstereospecific inducers of polymorphonuclear leukocyte migration orchemotaxis, lysosomal enzyme release, and degranulation. Additionally,these products induce the contraction of smooth muscle such as vascularand pulmonary tissue, and induce the generation of additionalinflammogens such as thromboxane A2 and prostacyclin. Lipoxygenaseproducts also interact with vasodilator prostanoids and other mediators,leading to the enhancement or amplification of the inflammatoryresponse.

Leukotrienes and the hydroxy- and hydroperoxyeicosatetraenoic acids playa major role in the pathogenesis of many disease conditions. Thesecompounds have been found in synovial fluid of rheumatoid joints, ininvolved skin of psoriatic patients, in inflammed colonic tissue, and atelevated levels in ischemic myocardial tissue. They are also mediatorsof allergic and asthmatic conditions.

Compounds and pharmaceutical compositions in accordance with the presentinvention inhibit lipoxygenase or the biosynthesis or biochemical actionof leukotrienes and, therefore, are useful in the treatment oramelioration of a number of diseases whose pathogenesis involves theproduction of the leukotrienes and other lipoxygenase-derived products.These lipoxygenase inhibitors aid in the prevention of tissue damage andinflammation which result from infiltration of leukocytes, release oftissue-digesting lysosomal enzymes, and changes in the permeability andcontractile state of smooth muscle tissue.

Specific conditions in which such lipoxygenase-inhibiting orleukotriene-antagonizing compounds and pharmaceutical compositions inaccordance with the present invention are useful include allergy;asthma; arthritis; skin disorders including psoriasis and acne;inflammation; inflammatory bowel diseases; pain; and cardiovasculardisorders including myocardial ischemia and infarction, angina,arrhythmias, stroke, and atherosclerosis.

Among the novel enolamides of the present invention are benzothiopyransand oxides thereof of Formula I having a moiety, Q, shown as substituentI₁ ; benzothiazine, 1,1-dioxide type compounds having a moiety, Q, shownas substituent I₂ ; benzofurans having a moiety, Q, shown as substituentI₃ ; benzo[b]thiophenes having a moiety, Q, shown as substituent I₄ ;benzopyrans having a moiety, Q, shown as substituent I₅ ;furo[3,2-b]indoles having a moiety, Q, shown as substituent I₆ ; andindole amides having a moiety, Q, shown as substituent I₇. Definitionsfor the various moieties of the present invention are found in thesubsequent descriptions herein.

Of the above defined enolamides the compounds of Formula I wherein Q isI₁ and wherein Q is I₄ are found to have leukotriene receptor affinitiesalso described herein as leukotriene antagonists.

Specific aryl carboxamides of benzothiopyran dioxides useful asantiinflammatory agents are described in British Pat. No. 1,338,996including an aryl amide having aryl as a naphthyl radical or an arylsubstituted by among others alkyl, aryl, or aralkyl. Additionally, U.S.Pat. No. 3,828,073 describes phenyl carboxamides of benzothiopyrans andtheir corresponding S-oxides also having an antiinflammatory utility.This patent includes the phenyl having specific alkyl, aryl, and aralkylsubstituents.

The dioxides of benzothiazines having various carboxamide moieties alsouseful as antiinflammatory agents are disclosed in U.S. Pat. Nos.3,591,584; 3,674,876; 3,803,205; 3,862,319; 3,891,637; 3,892,740;3,900,470; and 3,923,801 and also in British Pat. No. 2,118,544; BelgianPat. No. 751,300; and Japanese No. 58225-076. Among the variouscarboxamides are naphthyl and substituted phenyl carboxamides includingas phenyl substituents, an alkyl group.

U.S. Pat. No. 3,646,020 includes a lower alkyl substituted phenylcarboxamide as an intermediate. Lombardino et al, "Synthesis andAntiinflammatory Activity of Some 3-Carboxamides of2-Alkyl-4-hydroxy-2H-1,2-benzothiazine 1,1-dioxide," J. of MedicinalChem., Vol. 14, No. 12, pp 1171-1175 (1971) discloses naphthylcarboxamide and lower alkyl substituted phenyl carboxamides. Zinnes etal, "1,2-benzothiazines,6¹,3-carbamoyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxides asAntiinflammatory Agents," J. of Medicinal Chemistry, Vol. 16, No. 1, pp44-48 (1973) discloses phenyl substituted phenyl carboxamides.

Selected enolic benzofuran amides are disclosed by M. Pesson and M.Joannic, "New Derivatives of 2-carboxamido-3-hydroxybenzofuran" and inBritish Pat. No. 1,233,268 having choleretic activity.

Enolic indole amides generally are known. See M. Saxena and S. R. Ahmed,J. Med. Chem., 12, 1120 (1969). However, the compounds of the presentFormula I are not suggested by the limited disclosure of such knownamides.

Also falling within the scope of the present invention are thepharmaceutically acceptable acid and base addition salts of thecompounds of the present invention.

SUMMARY OF THE INVENTION

The present invention are compounds of the Formula I andpharmaceutically acceptable salts thereof wherein:

(1) y is one or two

(2) Q is a substituent selected from the group consisting of the FormulaI₁, I₂, I₃, I₄, I₅, I₆, and I₇ wherein a is zero, one or two; b is zero,one, two, three or four; X and Z are each independently hydrogen orlower alkyl; R₁ may be the same or different if b is two or more and isselected from a group consisting of alkyl of from one to four carbons,inclusive, alkoxy of from one to four carbons, inclusive, carboalkoxy offrom two to four carbons, inclusive, hydroxy, halogen, nitro, acyl offrom two through four carbons, inclusive, acylamino, of from two throughfour carbons, inclusive, amino, mono- and di-alkylaminohaving each alkylthe same or different from one to four carbons, inclusive,carboalkoxyamido, of from one to four carbons, inclusive,alkylsulfonamido of from one to four carbons, inclusive, alkylsulfinylof from one to four carbons, inclusive, alkylsulfonyl of from one tofour carbons, inclusive, and where a is one then R₁ may also be--(CH═CH--CH═CH)-- taken together with adjacent ring carbons to form abenzo radical; R₂ and R₃ are the same or different and are hydrogen,alkyl of from one to six carbons, inclusive, phenyl or benzyl;

(3) R₅ is hydrogen; alkyl of from one to four carbons, inclusive; alkoxyof from one to four carbons, inclusive; carbalkoxy of from two to fourcarbons, inclusive; hydroxy, halogen, or --(CH═CH--CH═CH)-- takentogether with adjacent carbons to form a benzo radical;

(4) R₆ is (a) alkyl of from six to twenty carbons, (b) --CH═CH--R₄, (c)--(CH₂)_(n) COR₄, or (d) --(CH₂)_(n) --R₄ wherein n is zero to four,inclusive, and R₄ is phenyl optionally substituted at the two throughsix positions by alkyl of from one to four carbons, inclusive, loweralkoxy carbonyl, carbalkoxy having alkoxy of from one to four carbons,inclusive, alkoxy or thioalkoxyl of from one to four carbons, inclusive,phenalkoxy, amino, monoalkyl- or dialkylamino having the alkyl of fromone to four carbons, inclusive, alkanoylamino of from two to sixcarbons, inclusive, carboxyl, halogen, hydroxy, hydroxyalkyl of from oneto four carbons, inclusive, alkanoyl of from one to four carbons,inclusive, nitro, alkanesulfonamido of from one to four carbons, orphenyl; and with the proviso that when Q is I₁ or I₂ having y as onethen R₆ cannot be alkyl, R₄ cannot be phenyl in --(CH₂)_(n) --R₄ and R₅cannot be --(CH═CH--CH═CH)-- taken together with adjacent carbons toform a benzo radical.

The embodiments of the present invention are compounds of Formula Iwherein Q is (a) I₁, (b) I₂, (c) I₃, (d) I₄, (e) I₅, (f) I₆, or (g) I₇,all having the above definitions.

One group of preferred compounds of Formula I include compounds whereinR₁, R₂, R₅ is hydrogen or the benzo radical, and X and Z are hydrogen, ais 2, y is 1, and R₆ is alkyl of from 6 to 20 carbons, inclusive, or--(CH₂)_(n) R₄ wherein n is two and R₄ is phenyl optionally substitutedby alkyl of from one to four carbons, inclusive, carboxyl, carboalkoxyof from one to four carbons, inclusive, chloro, alkoxy of from one tofour carbons, inclusive, hydroxy, or phenyl; or the pharmaceuticallyacceptable acid or base addition salts thereof.

Another group of preferred compounds of Formula I include compoundswherein R₁ and R₂ are hydrogen, y is 2, R₅ is hydrogen or the benzoradical; R₆ is alkyl of from 6 to 20 carbons, inclusive, or --(CH₂)_(n)--R₄ wherein n is 2 and R₄ is phenyl optionally substituted by alkyl offrom one to four carbons, inclusive, lower alkoxycarbonyl; carboxyl,carboalkoxy wherein the alkoxy is from one to four carbons, inclusive,alkoxy of from one to four carbons, inclusive, hydroxy; orpharmaceutically acceptable acid or base addition salts.

Thus, the more preferred compounds of Formula I are:

2H-1,2-Benzothiazine-3-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-2-methyl-1,1-dioxide.

2H-1,2-Benzothiazine-3-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-2-methyl-1,1-dioxide,compound with methanol (4:1).

2H-1,2-Benzothiazine-3-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-2-methyl-1,1-dioxide,L-arginate (salt) (1:1).

Benzo[b]thiophene-2-acetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-α-oxo.

Benzo[b]thiophene-2-acetamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-α-oxo.

Benzo[b]thiophene-2-acetamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-α-oxo, compoundwith 1-piperidineethanol (1:1).

2H-1-Benzothiopyran-3-carboxamide,3,4-dihydro-4-oxo-N-[4-[2-[4-(trifluoromethyl)phenyl]ethyl]phenyl]-1,1-dioxide.

2H-Furo[3,2-b]indole-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3,4-dihydro-7-hydroxy-3-oxo-4-phenyl.

Naphtho[2,3-b]furan-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy.

2H-1-Benzothiopyran-3-carboxamide,4-hydroxy-N-[4-[2-(2-naphthalenyl)ethyl]phenyl], 1,1-dioxide.

2H-1-Benzothiopyran-3-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-, 1,1-dioxide.

1H-Indole-2-acetamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-5,6-dimethyl-α-oxo.

2H-1-Benzopyran-3-acetamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-α-oxo.

2H-1-Benzothiopyran-3-carboxamide,N-[4-[2-(4-butoxyphenyl)ethyl]phenyl]-3,4-dihydro-4-oxo-1,1-dioxide.

2H-1-Benzothiopyran-3-acetamide, N-(4-decylphenyl)-4-hydroxy-α-oxo.

Naphtho[2,1-b]furan-2-carboxamide,1-hydroxy-N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl].

Naphtho[2,1-b]furan-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-1-hydroxy.

2H-1-Benzothiopyran-3-carboxamide,N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl]-3,4-dihydro-4-oxo-1,1-dioxide.

Benzo[b]thiophene-2-acetamides,N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl]-3-hydroxy-α-oxo.

2-Benzofuranacetamide,N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl]-2,3-dihydro-α3-dioxo.

2H-1,2-Benzothiazine-3-carboxamide,N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl]-4-hydroxy-2-hydroxy-2-methyl-1,1-dioxide.

Naphth[2,3-b]furan-2-acetamide,N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl]3-hydroxy-α-oxo.

Benzo[b]thiophene-2-acetamide,3-hydroxy-N-[4-[2-(4-hydroxy-3-methoxyphenyl)ethyl]phenyl]-α-oxo.

2H-1-Benzothiopyran-3-carboxamide,4-hydroxy-N-[4-[2-(4-hydroxy-3-methoxyphenyl)ethyl]phenyl]-1,1-dioxide.

However compounds of Formula I embodied by each of I₁, I₂, I₃, I₄, I₅,I₆, and I₇ contain preferred, more preferred, and/or most preferredcompounds and are, therefore, each discussed separately.

The most preferred compounds of Formula I wherein Q is I₁ include thefollowing species:

N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide.

N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl]-3,4-dihydro-4-oxo-(2H)-1-benzothiopyran-3-carboxamide-1,1-dioxide.

N-[4[2-(4-biphenyl)ethyl]phenyl]-3,4-dihydro-4-oxo-(2H)-1-benzothiopyran-3-carboxamide-1,1-dioxide.

N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3,4-dihydro(2H)-1-benzothiopyran-3-carboxamide-1,1-dioxide.

N-[4-(n-decyl)phenyl]-3,4-dihydro-4-oxo(2H)-1-benzothiopyran-3-carboxamide-1,1-dioxide.

N-[4-(n-decyl)phenyl]acetamide-3,4-dihydro-4-oxo-(2H)-1-benzothiopyran-.alpha.-oxo-1,1-dioxide.

N-[4-[2-(4-chlorophenyl)ethyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide.

N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide.

4-Hydroxy-4-[2-(2-naphthalenyl)ethyl]phenyl]-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide.

N-[4-[2-(3,4-dimethylphenyl)ethyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide.

N-[4-[2-(3-trifluoromethylphenyl)ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide.

4-hydroxy-N-[4-[2-(4-hydroxy-3-methoxyphenyl)ethyl]phenyl]-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide.

N-[4-[2-(2,4-dichlorophenyl)ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide.

N-[3-[2-(3,4-dichlorophenyl)ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide.

N-[4-[3-(3,4-dichlorophenyl)propyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide.

Most preferred compound of Formula I wherein Q is I₂ are:

N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide,1,1-dioxide.

N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide,1,1-dioxide.

N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide,1,1-dioxide.

N-[2-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.

N-[2-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide,1,1-dioxide.

N-(4-decylphenyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide,1,1-dioxide.

N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide,1,1-dioxide.

Compounds of Formula I wherein Q is I₂ which are preferred include:

2H-1,2-Benzothiazine-3-carboxamide,4-hydroxy-N-[4-[2-(4-hydroxy-3-methoxyphenyl)ethyl]phenyl]-2-methyl-,1,1-dioxide, and

2H-1,2-Benzothiazine-3-carboxamide,4-hydroxy-N-[4-[2-(4-hydroxy-3-methoxyphenyl]ethenyl]phenyl]-2-methyl-,1,1-dioxide.

More preferred compounds of Formula I wherein Q is I₃ are:

2-Benzofuranacetamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-2,3-dihydro-α,3-dioxo-;

2-Benzofuranacetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-αoxo-;

2-Benzofuranacetamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-7-methoxy-αoxo-

2-Benzofurancarboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-;

2-Benzofuranacetamide,N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl]-2,3-dihydro-α,3-dioxo-;

Naphtho[2,3-b]furan-2-acetamide,N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl]-3-hydroxy-α-oxo-.

The most preferred compounds of Formula I wherein Q is I₃ are:

Naphtho[2,3-b]furan-2-carboxamide,N-[4-[2-(3,4-dimethoxyphenyl]ethyl]phenyl]-2,3-dihydro-3-oxo;

Naphtho[2,3-b]furan-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl]ethyl]phenyl]-3-hydroxy;

Naphtho[2,1-b]furan-2-carboxamide,N-[4-[2-(3,4-dimethoxyphenyl]ethyl]phenyl-1-hydroxy;

Naphtho[2,1-b]furan-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl]ethyl]phenyl-1-hydroxy;

Naphtho[1,2-b]furan-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl]ethyl]phenyl-3-hydroxy;

Naphtho[2,1-b]furan-2-carboxamide,N-[4-[2-(4-hydroxy-3-methoxyphenyl)ethyl]phenyl-1,2-dihydro-1-oxo.

Most preferred compounds of Formula I wherein Q is I₄ are:

Benzo[b]thiophene-2-acetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-α-oxo-;

Benzo[b]thiophene-2-acetamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-α-oxo-;

Benzo[b]thiophene-2-carboxamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-;

Benzo[b]thiophene-2-carboxamide,N-[3-[2-(3,4-dichlorophenyl)ethyl]phenyl]-3-hydroxy-.

Most preferred compounds of Formula I wherein Q is I₅ are:

N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-α-oxo-2H-1-benzopyran-3-acetamide;

More preferred compounds of Formula I wherein Q is I₆ are:

2H-Furo[3,2-b]indole-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3,4-dihydro-3-oxo-4-phenyl.

2H-Furo[3,2-b]indole-2-carboxamide,N-[4-[2-(4-methoxyphenyl)ethyl]phenyl]-3,4-dihydro-4-methyl-3-oxo.

2H-Furo[3,2-b]indole-2-carboxamide,N-[4-[2-(4-hydroxyphenyl)ethyl]phenyl]-3,4-dihydro-4-methyl-3-oxo.

2H-Furo[3,2-b]indole-2-acetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3,4-dihydro-4-methyl-α,3-dioxo.

2H-Furo[3,2-b]indole-2-acetamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3,4-dihydro-4-methyl-α,3-dioxo.

2H-Furo[3,2-b]indole-2-acetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3,4-dihydro-7-methoxy-α,3-dioxo-4-phenyl.

Most preferred compounds of Formula I wherein Q is I₆ are:

4H-Furo[3,2-b]indole-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-4-methyl;

4H-Furo[3,2-b]indole-2-carboxamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-4-methyl;

2H-Furo[3,2-b]indole-2-carboxamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3,4-dihydro-7-methoxy-3-oxo-4-phenyl;

2H-Furo[3,2-b]indole-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3,4-dihydro-7-hydroxy-3-oxo-4-phenyl;

2H-Furo[3,2-b]indole-2-acetamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3,4-dihydro-7-hydroxy-α,3-dioxo-4-phenyl.

More preferred compounds of Formula I wherein Q is I₇ are:

1H-Indole-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-1-methyl;

1H-Indole-2-acetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-5,6-dimethyl-α-oxo;

1H-Indole-2-acetamide, N-(4-decylphenyl)-3-hydroxy-5,6-dimethyl-α-oxo;

1H-Indole-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy;

1H-Indole-2-acetamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-5,6-dimethyl-α-oxo.

The compounds of the present invention include certain substituted4-oxo- or 4-hydroxy-benzothiazine-3-carboxamide, 1,1-dioxides. Althoughdepicted in the enol form, with a hydroxy group at respective positionsin I₁, I₂, I₃, I₄, I₅, I₆, and I₇ within the structural Formula I above,compounds of the present invention are capable of existence in both theketo and enol tautomeric forms. The compounds may thus, for example, benamed as either 3,4-dihydro-4-oxo-2H-1-benzothiazine-3-carboxamides inthe keto form or as 4-hydroxy2H-1-benzothiazine-3-carboxamides in theenol form, and may be depicted in structural formulae in either form.The present invention contemplates both forms of the compounds, and thetwo forms are considered equivalent for purposes of the presentinvention.

The present invention is also a pharmaceutical composition comprising aneffective amount of a compound having the Formula I as defined abovetogether with a pharmaceutically acceptable carrier. An effectiveamaount is the amount useful for treating or ameliorating a number ofdiseases or conditions comprising an inhibition of a lipoxygenase effector comprising a binding of a leukotriene receptor. The diseases orconditions are readily recognized for the pathogenesis affected by theinhibitory lipoxygenase effect and affected by the binding of aleukotriene receptor, as recited herein.

Thus, in accordance with the present invention, another aspect of theinvention, provides a method of administering to mammals, includinghumans, in need of treatment or amelioration of diseases or conditionsan amount effective for treatment of the diseases or conditions of acompound or composition having the Formula I as defined above. The needis evident for diseases or conditions benefiting from inhibition of alipoxygenase effect.

By virtue of the activity of the compounds having the Formula I of thepresent invention as leukotriene D4 antagonists, and inhibitors of5-lipoxygenase and histamine release from basophils the compounds areuseful in treating asthmas and allergies as well as cardiovasculardisorders, migraine, and immunoinflammatory conditions. See B.Samulesson, "Leukotrienes: Mediators of Immediate HypersensitivityReactions and Inflammation, "Science" Vol. 220, p 568 (1983); P. J.Piper, "Leukotrienes," Trends in Pharmaceutic Sciences, pp 75 & 77(1983), and J. L. Romson, et al, "Reduction of the Extent of IschemicMyocardial Injury by Neutrophil Depletion in the Dog," Circulation, Vol.67, pp 1016 (1983).

Additionally, the activity, of the compounds having the Formula I of thepresent invention is determined by the well known leukotriene receptorbinding assay that is described by R. F. Bruns, W. J. Thomsen and T. A.Pugsley in Life Sciences, 33, 645 (1983) or the Herxheimer in vivoantiallergy test described in H. Herxheimer, J. Physiol. (London), Vol.177, p. 251 (1952).

The antiasthma and antiallergic activity provides methods of treatmentfor hypersensitivity reaction having broad symptoms. For example, thesymptoms may include dermatitis, lacrimation, nasal discharge, coughing,sneezing, nausea, vomiting, diarrhea, difficulty in breathing, pain,inflammation, and in severe cases, anaphylatic shock and circulatorycollapse. The symptoms may be found in man as well as other animalssuffering from bronchial asthma, seasonal pollinosis (e.g., hayfever),allergic rhinitis, urticoria, allergic conjunctivitis, food allergies,and anaphylactoid reactions.

Likewise, the activity of the compounds of Formula I provides a methodof treatment for cardiovascular disorders, particularly ischemia andmyocardial infarctions. The symptoms of a subject having acardiovascular disorder may be determined by special diagnosticprocedures directed to subjects having a history, general physicalappearance and then detailed deviations from normal appearancesuggesting a cardiovascular disorder. Such disorders are also found inman as well as other mammals. Symptoms of the disorders are describedextensively in The Merck Manual 14th ed, (1982).

Further, method of treatment is provided by the compounds of Formula Iherein for migraine and inflammation. The symptoms requiring treatmentfor these purposes are also readily recognized, particularly formigraine in man and/or inflammation in man as well as other mammals.

Pharmaceutical compositions which also are the present invention areprepared from the compound of Formula I and salts thereof described asthe present invention having inert pharmaceutical carriers. Thecompositions may be either solid or liquid.

A physician or veterinarian of ordinary skill readily determines asubject who is exhibiting symptoms described herein. Regardless of theroute of administration selected, the compounds of the present inventionare formulated into pharmaceutically acceptable dosage forms byconventional methods known to the pharmaceutical art.

The compounds can be administered in such oral unit dosage forms such astablets, capsules, pills, powders, or granules. They also may beadministered rectally or vaginally in such forms as suppositories orbougies; they may also be introduced parenterally (e.g., subcutaneously,intravenously, or intramuscularly), using forms known to thepharmaceutical art. They are also introduced directly to an affectedarea (e.g., in the form of eye drops or by inhalation). For thetreatment of asthma or allergies such as erythema, the compounds of thepresent invention may also be administered topically in the form ofointments, creams, gels, or the like. However, in general, the preferredroute of administration is orally.

An effective but nontoxic quantity of the compound is employed intreatment. The ordinarily skilled physician or veterinarian will readilydetermine and prescribe the effective amount of the compound to preventor arrest the progress of the condition for which treatment isadministered. In so proceeding, the physician or veterinarian couldemploy relatively low dosages at first, subsequently increasing the doseuntil a maximum response is obtained.

Initial dosages of the compounds of the invention having Formula I areordinarily in the area of 1 mg up to 3 g per day orally, preferably 1 mgto 500 mg per dose orally, given from one to four times daily or asneeded. When other forms of administration are employed equivalent dosesare administered.

The compounds of the invention are capable of forming bothpharmaceutically acceptable acid addition and/or base salts. Base saltsare formed with metals or amines, such as ammonium, alkali, and alkalineearth metals or organic amines. Examples of metals used as cations aresodium, potassium, magnesium, calcium, and the like. Examples ofsuitable amines are N,N'dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamine, N-methylflucamine, andprocaine.

Pharmaceutically acceptable acid addition salts are formed with organicand inorganic acids.

Examples of suitable acids for salt formation are hydrochloric,sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicyclic,malic, gluconic, fumaric, succinic, ascorbic, maleic, methanesulfonic,arginine, and the like. The salts are prepared by contacting the freebase form with a sufficient amount of the desired acid to produce eithera mono or di, etc salt in the conventional manner. The free base formsmay be regenerated by treating the salt form with a base. For example,dilute solutions of aqueous base may be utilized. Dilute aqueous sodiumhydroxide, potassium carbonate, ammonia, and sodium bicarbonatesolutions are suitable for this purpose. The free base forms differ fromtheir respective salt forms somewhat in certain physical properties suchas solubility in polar solvents, but the salts are otherwise equivalentto their respective free base forms for purposes of the invention.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms. In general, the solvatedforms, including hydrated forms and the like are equivalent to theunsolvated forms for purposes of the invention.

Finally, the methods of preparation and selected novel intermediates forpreparation for compounds of Formula I as defined above are also thepresent invention.

Generally, a method of preparation of the compounds of Formula I asdefined above can be accomplished as shown in Scheme I wherein Q, y, R₅,and R₆ are as defined above and R is hydrogen, lower alkyl, or phenyl.

When R is hydrogen the preparation of the compound of Formula I shown inScheme I may be accomplished by reacting the acid II wherein R ishydrogen with dicyclohexylcarbodiimide or carbonyldiimidazole and thedesired compound of Formula III in an inactive solvent, such astetrahydrofuran, methylene chloride or ethylene dichloride or mixturesthereof under nitrogen at from about -10° C. to about room temperaturefor from 50 minutes to 24 hours. Optimum conditions vary withinreasonable experimentation depending upon the reactants.

Alternatively, when R is lower alkyl or phenyl the preparation of thecompound of Formula I shown in Scheme I may be accomplished by reactingthe ester II wherein R is lower alkyl or phenyl in the presence of butyllithium, diisopropylamine, and the desired aniline of Formula III. Aninert organic solvent such as tetrahydrofuran is used in the reactionwhich is maintained at ice bath temperature with an ice bath for fromten minutes to two hours. See, for example, K. W. Yank, et al,Tetrahedron Letters, 1791 (1970).

Specific variations within the above general description may include,for example, preparation of compounds of Formula I wherein R₄ includesphenyl optionally substituted by at least one hydroxy group by treatmentof corresponding methoxy groups to replace the methyl by hydrogen withboron tribromide in dichloroethane or dichloromethane, hydrobromic acidor trimethylsilyliodide using appropriate conditions. For example, seealso M. V. Bhatt and S. U. Kulkarmi, Synthesis (4), 249 (1983) for areview of the cleavage of ethers.

The intermediates of Formula III wherein R₆ is alkyl of from six totwenty carbons, inclusive, are known or can be readily prepared by anordinarily skilled artisan. However, the novel intermediate of FormulaIII wherein R₆ is --CH═CH--R₄ and --(CH₂)_(n) --R₄ or (CH₂)_(n) COR₄ areprepared by a synthetic sequence as shown for III₂, III₃, and III₄ inSchemes III or IV, respectively. More specifically, the compound ofFormula IV₁, wherein R₇ are the optional substituents for the phenyl asdefined above for R₄, a is an integer of from 0 to 5, and R₅ is asdefined above; is prepared in a manner shown in Scheme II which isanalogous to the method disclosed by P. Pfeiffer and S. Sergiewskaya,Ber., 44: 1109 (1911). Subsequent reduction of compounds of Formula IV₁is accomplished by either H₂ and Raney nickel or iron and hydrochloricacid or dithionate to produce the compound of Formula III₂ or FormulaIII₃, respectively, wherein R₇ and R₅ are as defined above. Thereduction is carried out in conditions within the ranges known for thereagents. Reduction of IV₁ by catalytic hydrogenation using a Raneynickel catalyst within the range of conditions known for this reductionproduces compounds of Formula III₂ reducing both the nitro-moiety andunsaturation of the hydrocarbon chain in --CH═CH--R₄ of the R₆definition with the compound of Formula I above. Reduction of IV₁ withiron and HCl or dithionate selectively reduces the nitro moiety.

Intermediate compounds of Formula III₄ wherein R₅ and R₇ are as definedabove are obtained by catalytic addition of H₂ to the compound ofFormula IV₂ over a palladium/carbon catalyst using conditions withinthose known or without unreasonable experimentation for hydrogenationusing H₂ with these catalysts. Scheme IV shows the hydrogenation of theintermediate precursor having Formula IV₂ to obtain III₄. The compoundsof Formula IV₂ having R₅ and R₇ as defined above are prepared in amanner analogous to known Friedel-Crafts acylation methods as disclosedby Tadkod, et al, J. Karnatack Univ., 3: 78-80 (1958). The Scheme IValso shows preparation of the compounds of Formula IV₂.

The intermediates of Formula II wherein Q, y, and R are as defined aboveare synthesized by a process relative to the definitions of Q shown from(a) through (g) above.

For example, generally, the compounds of Formula II wherein Q is I₁ asdefined above are prepared by a process shown in Scheme V. The startingmaterial of Formula XLII₁, wherein R₁ is as defined above, is preparedin a process analogous to the method described by L. H. Helberg and A.Juarez, in Tetrahedron Letters, 40: 3553 (1974). The treatment of thematerial of Formula XLII₁ wherein R₁ is as defined above, by dropwiseaddition of oxalyl chloride to the material in an organic solvent suchas diethyl ether, results in the compound of Formula XXXII₁ wherein R₁is defined above. The addition is made over a period of about 50 minutesat room temperature under nitrogen. The mixture is stirred further forfrom 15 hours to 24 hours. Controlled oxidation of the compound ofFormula XXXII₁ with, for example, m-chloroperbenzoic acid producescompounds of Formula XXII₁ wherein R₁ is as defined above and a is one.However, the use of excess oxidizing agent, even in the case ofm-chloroperbenzoic acid, produces the compound of Formula XXII₁ where R₁is as defined above but a is equal to two. Such oxidation proceeds undernitrogen in an inert organic solvent such as dichloromethane at atemperature of about 0° C. to -10° C. preferably about 5° C. Thereaction is controlled by the dropwise addition of the oxidation agent.

The compound of Formula XXXII₁, XXII₁, or II₁ is subsequently reacted asshown for the compound of Formula II in Scheme I, that is, in the formof the ketolactone or as the ester thereof having the Formula XXXII₁/XXII₁ /II₁ wherein R₁, a, and R is as defined above. The esters ofFormula II₁ are prepared by the methods analogous to those detailed byI. W. S. Still and M. T. Thomas, J. Org. Chem., 33: 2730 (1968).

The intermediates of Formula II wherein Q is I₂ as defined above aredisclosed in various references as discussed above or can be readilyprepared in a manner analogous to known procedures.

Likewise, intermediates of Formula II wherein R₁ is as defined above, Qis I₃ wherein R is lower alkyl is known in the literature or can bereadily prepared from known processes. Similarly, a compound of FormulaXII₃ wherein R₁ is as defined above are known. See P. O. Corcoran, etal, J. Org. Chem., 27, p. 586 (1962) and F. Dallacker and W. Korb, Ann.,694, 98 (1966). Reactions of a compound of Formula XII₃ to prepare acompound of Formula I wherein Q is I₃ is shown in Scheme VI. Theconditions of the reactions shown in Scheme VI may be analogous to thosedescribed in Wiseman, et al, J. Med. Chem., 16, p. 131 (1973). Thereactant of the Formulae XIII and XXIII may be prepared from theCompound III by methods analogous to those known for the preparation ofamides.

The intermediates of Formula II wherein R₄ is as defined above and Q isI₄ are known can be prepared by known methods when y is one or twoprepared in a manner analogous to the procedure disclosed by B. Lamm andC. J. Aurell, in Acta Chemica Scand., Ser. B., p. 435 (1982) or byadding a suspension of 5-chloro-3-hydroxybenzo[b]thiophene orappropriately substituted variation in an organic solvent such as etherto a mixture prepared by adding a lower dialkyl ester or oxalic acid toa suspension of sodium methoxide in anhydrous ether all under nitrogen.Generally, the temperatures of the suspensions and mixture thereof ismaintained at from about -10° to about 15° C. during the mixing andsubsequently stirred at room temperature for about an hour. The5-chloro-3-hydroxybenzo[b]thiophene or appropriately substitutedvariation refers to a compound wherein R₁ is present and is as definedabove. Such a thiophene is either known or prepared by known methods.See L. H. Werner, et al, J.A.C.S., 79, 1679 (1957) and M. S. ElShanta etal, J. Chem. Soc. (C) 2364 (1967).

The intermediates of Formula II wherein R is as defined above and Q isI₅ are known or can be prepared by known methods when y is one. However,these intermediates when y is two are novel and are prepared as shown inScheme VII. R is in a ketolactone form in Scheme VII. The preparation ofthe compound of Formula XXII₅ wherein R₁ is as defined above isanalogous to that described by L. H. Helberg and A. Zuarez. TetrahedronLetters, 40, 3553 (1974). Oxalyl chloride is added dropwise over aperiod of about one-half to one hour to a suspension of the compound ofFormula XXII₅ in an anhydrous organic solvent such as ether. Thetemperature of the suspension during addition is about room temperature.

The preparation of the intermediate of Formula II wherein R is asdefined above and Q is I₆ is described in copending U.S. patentapplication Ser. No. 456,121 now issued as U.S. Pat. No. 4,503,236(1985). Such intermediates can be used as described above in Scheme I orcan be further decarboxylated to form a compound of Formula XII₆ (seeScheme VIII) wherein R₁ and R₂ are as defined above. The decarboxylationis analogous to that discussed above in preparing an intermediate ofFormula XII₃. The compound of Formula XII₆ is subsequently reacted asshown in Scheme VIII with a compound of Formula XIII or of Formula XXIIIpreviously described and shown as reactants in Scheme VI. Again see E.H. Wiseman, et al, J. Med. Chem., 16, 131 (1973).

Finally, the intermediates of Formula II wherein R is as defined aboveand Q is I₇ when y is one are known or readily prepared from knownprocesses. See the disclosure by P. Friedlander and K. Kunz, Chem. Ber.,55, 1597 (1922) and A. Etiene, Bull. Soc. Chim. Fr., 15, 651 (1948) tocompounds of Formula II having Q equal to I₇ wherein R₃ is hydrogen.Protection of the enolic OH is readily accomplished by known protectinggroups so the reactions of Scheme I as discussed above can proceed. Thecompounds of Formula II having Q as I₇ wherein y is two are alsogenerally known or can be made by known processes. See, for example, N.Buhler, et al, U.S. Pat. No. 4,260,544 (1981).

Compounds wherein X is lower alkyl can be prepared by an appropriateprocess step analogous to known processes.

Under certain circumstances it is necessary to protect either the N or Oof intermediates in the above noted process with suitable protectinggroups which are known. Introduction and removal of such suitable oxygenand nitrogen protecting groups are well known in the art of organicchemistry; see for example "Protective Groups in Organic Chemistry," J.F. W. McOmie, ed., (New York, 1973), pages 43ff, 95ff; J. F. W. McOmie,Advances in Organic Chemistry, Vol. 3, 191-281 (1963); R. A. Borssonas,Advances in Organic Chemistry, Vol. 3, 159-190 (1963); and J. F. W.McOmie, Chem. & Ind., 603 (1979).

Examples of suitable oxygen protecting groups are benzyl,t-butyldimethylsilyl, ethoxyethyl, and the like. Protection of an N-Hcontaining moiety is necessary for some of the processes describedherein for the preparation of compounds of this invention. Suitablenitrogen protecting groups are benzyl, triphenylmethyl, trialkylsilyl,trichloroethylcarbamate, trichloroethoxycarbonyl, vinyloxycarbamate, andthe like.

Under certain circumstances it is necessary to protect two differentoxygens with dissimilar protecting groups such that one can beselectively removed while leaving the other in place. The benzyl andt-butyldimethylsilyl groups are used in this way; either is removable inthe presence of the other, benzyl being removed by catalytichydrogenolysis, and t-butyldimethylsilyl being removed by reaction with,for example, tetra-n-butylammonium fluoride.

In the process described herein for the preparation of compounds of thisinvention the requirements for protective groups are generally wellrecognized by one skilled in the art of organic chemistry, andaccordingly the use of appropriate protecting groups is necessarilyimplied by the processes of the charts herein, although not expresslyillustrated.

The products of the reactions described herein are isolated byconventional means such as extraction, distillation, chromatography, andthe like.

The salts of compounds of Formula I described above are prepared byreacting the appropriate base or acid with a stoichometric equivalent ofthe acid enol or N base compounds of Formula I, respectively, to obtainpharmacologically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

By the term, "alkyl of from 6 to 20 carbons, inclusive" is meant anybranched or unbranched saturated hydrocarbon grouping having the notednumber or carbons, such as hexyl, heptyl, octyl, nonyl, decyl, dodecyl,and the like, and isomers thereof.

The term "alkoxy of from one to four carbons, inclusive" means methoxy,ethoxy, propoxy, or butoxy, and isomers thereof attached to the parentmolecular residue through an oxygen atom. Thioalkoxy of from one to fourcarbons, inclusive, is the same except attached through a sulfur atom.

The term "monoalkyl- or dialkyl-amino having of from one to fourcarbons, inclusive," means respectively, one or two alkyl groups, aspreviously defined for of from one to four carbons, inclusive, attachedto the parent molecular residue through a nitrogen atom.

The term "alkanoyl of from one to four carbons, inclusive," means abranched or unbranched alkyl, as previously defined for of from one tofour carbons, inclusive, attached to the parent molecule residue throughthe carbonyl group.

The term "hydroxyalkyl of from one to four carbons, inclusive," is anhydroxy attached through an alkyl group, as previously defined for offrom one to four carbons, to the parent molecular residue.

The term "alkanoylamino of from two to six carbons, inclusive," means analkanoyl, as previously defined by including also pentyl or hexyl andisomers thereof among the alkyl attached to the parent molecule residuethrough the amino group.

The term "carboxyalkoxy having alkoxy of from one to four carbons,inclusive," means an alkyl, as previously defined for alkyl of from oneto four carbons, inclusive, attached to the oxygen atom of an estergroup, through which the alkyl is attached to the parent molecularresidue.

The term "alkanesulfonamide of from one to four carbons, inclusive,"means an alkyl, as defined above for of from one to four carbons,attached to the nitrogen atom or a sulfonamide moiety and thus throughthe sulfur atom to the parent molecular residue.

"Halogen" means fluorine, chlorine, bromine, iodine, or trifluoromethyl.

"Carboalkoxyamide of from one to four carbons, inclusive," means analkyl, as defined above for of from one to four carbons, inclusive,attached to the oxygen atom of an ester group which carboxyl is in turnattached to the parent molecule residue through an amino group.

"Alkyl sulfinyl" and "alkyl sulfonyl" are respectively, an alkylattached to the parent residue molecule through a sulfinyl and sulfonylgroup.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention is further elaborated by the representative examples asfollows. Such examples are not meant to be limiting thereto.

I. Preparation of compounds of Formula IV

A. For compounds of Formula IV, see Scheme II.

PREPARATION A 1,2-Dimethoxy-4-[2-(4-nitrophenyl)ethenyl]benzene (SeeScheme II, Formula IV₁, wherein c is two, R₇ is methoxy, R₅ is hydrogen)

A mixture of 272 g (1.5 mole) of p-nitrophenylacetic cid and 249 g (1.5mole) of 3,4-dimethoxybenzaldehyde in a 2.0 l nitrogen-filled flask washeated to 60° C. (temperature of reaction mixture) on the steam bath.Piperidine (150 ml; 129 g, 1.52 mole) was added to the warmreactionmixture in small portions over 15 minutes. After ˜50 ml ofpiperidinehad been added, a mild exotherm developed, and the temperatureof the reaction mixture rose to 95° C. without external heating. Thesteambath was replaced by a heating mantle, and the mixture was heatedto refluxover 15 minutes, then maintained at 110°-120° C. for fourhours. The reaction mixture was cooled to 70° C. and stirred vigorouslywhile 500 ml of methanol was added. After cooling the mixture in ice,the precipitate that formed was filtered, stirred in 1.0 l of freshmethanol, and refiltered. There was obtained 219 g (51% yield) of olefinproduct, mp 132°-134° C.

PREPARATION B 1,2-Dichloro-4-[2-(4-nitrophenyl)ethenyl]benzene (SeeScheme II, Formula IV₁ wherein c is two, R₇ is chloro, and R₅ ishydrogen)

Prepared by the procedure described in Preparation A, fromp-nitrophenylacetic acid (125 g, 0.69 mole) and 3,4-dichlorobenzaldehyde(121 g, 0.69 mole). There was obtained 70 g (35% yield) of the product,mp197°-199° C.

In an analogous manner to that found in above Preparation A startingmaterials the following compounds of Formula IV₁ are prepared (seeScheme II).

PREPARATION C 4-[2-[(4-Nitrophenyl)ethenyl][1,1-biphenol] mp 238°-239°C. PREPARATION D1-Methoxy-4-[2-(4-nitrophenyl)ethenyl]-2-(phenylmethoxy)benzene, mp139°-144° C. PREPARATION E1,2-Dimethyl-4-[2-(4-nitrophenyl)ethenyl]benzene, mp 113°-115° C.PREPARATION F 1,3-Dimethoxy-5-[2-(4-nitrophenyl)ethenyl]benzene, mp145°-146° C. PREPARATION G 2-[2-(4-Nitrophenyl)ethenyl]naphthalene, mp168°-170° C. PREPARATION H1,2,3-Trimethoxy-5-[2-(4-nitrophenyl)ethenyl]benzene, mp 192°-195° C.PREPARATION I 1,2-Dimethoxy-3-[2-(4-nitrophenyl)ethenyl]benzene, mp143°-145° C. PREPARATION J2,4-Dimethoxy-1-[2-(4-nitrophenyl)ethenyl]benzene, mp 107°-110° C.PREPARATION K 1,2-Dimethoxy-4-[2-(2-nitrophenyl)ethenyl]benzene, mp134°-137° C.

B. For compounds of Formula IV₂ see Scheme IV

PREPARATION L N-[2-Methoxy-5-[(4-nitrophenyl)acetyl]phenyl]acetamide(See Scheme IV, Formula IV₂ Wherein c is two, R₇ is methoxy andAcetamide, n is one, and R₅ is hydrogen)

A mixture of anhydrous AlCl₃ (36 g, 270 mmol) and 50 ml of CH₂ Cl₂ iscooled to 0° in an ice bath. 2-Acetylanisidine (33 g, 200 mmol) is addedto the stirring mixture. A solution of 39.9 g (200 mmol) of4-nitrophenylacetyl chloride in 130 ml of CH₂ Cl₂ is added slowly to thecooled reaction mixture. The reaction mixture is stirred at 0° C. for0.75 hour and 22 hours at room temperature. The reaction mixture ispoured onto a mixture of 800 ml ice and 40 ml concentrated hydrochloricacid and allowed to stir for 1.25 hours before extraction with CH₂ Cl₂.The CH₂ Cl₂ extract is evaporaed to a dark oily residue whichcrystallized from MeOH to give 28 g(52%) of a yellow solid. Furtherrecrystalliztion from MeOH gave the pure product, mp 200°-203° C.

In a manner analogous to that found above in Preparation L usingappropriate starting materials the following compounds of Formula IV₂areprepared.

PREPARATION M 1-(3,4-Dimethoxyphenyl)-3-(4-nitrophenyl)propanone,mp-126°-132° C. PREPARATION N1-(3,4-Dimethoxyphenyl)-4-(4-nitrophenyl)butanone, mp 109°-112° C.

II. Preparation of Compounds of Formula III

A. For compounds of Formula III₂ and III₃ see Scheme III.

PREPARATION 1 4-[2-(3,4-Dimethoxyphenyl)ethyl]benzeneamine (See SchemeIII Formula III₂ Wherein c is 2, R₇ is 3,4-dimethoxy, and R₅ is Hydrogen

A mixture of 19.4 g (0.068 mole) of1,2-dimethoxy-4-[2-(4-nitrophenyl)etheno]benzene as prepared inPreparation A above, and 0.20 g 10% Pd/C catalyst in 200 ml ofN,N-dimethylformamide was hydrogenated at 55 psig H₂ pressure for 16hours. The catalyst was removed by filtration, and the filtrate wasevaporated. Recrystallization of the residue from methanol yielded 12.3g (70% yield) of the amine product, mp 116°-117° C.

PREPARATION 2 4-[2-(3,4-Dichlorophenyl)ethyl]benzenamine (See SchemeIII, Formula III₂ Wherein R₇ is 3,4-dichloro, c is two, and R₅ isHydrogen)

A mixture of 62.3 g (0.21 mole) of1,2-dichloro-4-[2-(4-nitrophenyl)etheno]benzene as prepared inPreparationB above, and 2.0 g of Raney Nickel catalyst in 935 ml oftetrahydrofuran was hydrogenated at 65 psig H₂ pressure for 20 hours.The catalyst was removed by filtration, and the filtrate was evaporated.Recrystallization of the residue from hexane/dichloromethane yield 49 g(87% yield) of the amine product, mp 73°-75° C.

In a manner analgous to that found above in Preparations 1 and 2 usingappropriate starting materials, as prepared in Preparations C through Fcorresponding to the following Preparations 3 through 6 and thereafteras indicated for Preparations 8 through 18. The following compounds ofFormula III₂ are prepared.

PREPARATION 3 4-[2-(1,1'-Biphenyl)-4-ylethyl]benzenamine, mp 109°-111°C. PREPARATION 4 4-[2-(2-Naphthylenyl)ethyl]benzeneamine, mp 123°-125°C. PREPARATION 5 4-[2-(3-Hydroxy-4-methoxyphenyl]benzenamine, mp152°-154° C. PREPARATION 6 4-[2-(3-Methoxyphenyl)ethyl]benzenamine, mp49°-51° C. PREPARATION 7 4-[2-(3,4-Dihydroxyphenyl)ethyl]benzenamine asan acetate salt, mp 216°-218° C.

A mixture of 20 g (78 mmol) of 4-[2-[3,4-dimethoxyphenyl)ethyl]anilinewhich is prepared in Preparation 1 above and 300 ml of of 48%hydrobromic acid is stirred at reflux under nitrogen for seven hours andat room temperature overnight. The resultant precipitate is collected,washed withether, and redissolved in 1N.NaOH. The solution is acidifiedto pH 6 with glacial HOAc and the resultant precipitate is collected ascrude product. Recrystallization from H₂ O and then from MeOH yields the4-[2-(3,4-dihydroxyphenyl)ethyl]benzenamine as an acetate salt; yield,13.4 g (76%), mp 216°-218° C.

PREPARATION 7A 1,2-Benzenediol, 4-[2-(4-aminophenyl)ethyl]diacetate

4-[2-(3,4-Dihydroxyphenyl)ethyl]benzenamine hydrobromide as prepared inPreparation 7 above (53.3 g, 0.17 mole) is added to a stirred solutionof acetylbromide (67.6 g, 0.549 mole) and trifluoroacetic acid (670 ml).The mixture is stirred at room temperature for 3.5 hours. The excess ofacetylbromide and trifluoroacetic acid is then removed at <25° C. underreduced pressure. The residue after trituration with ether (˜1 l) gave63.47 g of a white solid, mp 165° C. (dec). This hydrobromide salt issuspended in ˜1 l of ice-water and ˜1.5 l of ether andcarefully madebasic with 1N sodium bicarbonate solution while the temperature ismaintained below 10° C. The ether layer is separatedand the aqueouslayer is extracted with ether. The combined ether extract is dried andevaporated to give 46 g (85.3%) of a pure product, mp 100°-1° C.Recrystallization from methylene chloride-methanol gives 24.9 g (46.3%)of analytically pure product, mp 100°-1° C.

PREPARATION 8 4-[2-(2,3-Dimethoxyphenyl)ethyl]benzenamine.HCl, mp135°-136°C.

The starting material,1,2-dimethoxy-3-[2-(4-nitrophenyl)ethenyl]benzene, is as prepared inPreparation I above.

PREPARATION 9 4-[2-(2,4-Dimethoxyphenyl)ethyl]benzenamine, mp 56°-58° C.

The starting material,2,4-dimethoxy-1-[2-(4-nitrophenyl)ethenyl]benzene, is as prepared inPreparation J above.

PREPARATION 10 4-[2-(3,4,5-Trimethoxyphenyl)ethyl]benzenamine, mp91°-93° C.

The starting material,1,2,3-trimethoxy-5-[2-(4-nitrophenyl)ethenyl]benzene, is as prepared inPreparation H above.

PREPARATION 11 4-[2-(3,5-dimethoxyphenyl)ethyl]benzenamine.HCl, mp155°-157°C.

The starting material,1,3-dimethoxy-4-[2-(4-nitrophenyl)ethenyl]benzene, is prepared in amanner analogous to Preparations A through K.

PREPARATION 12 4-[2-(2-Chlorophenyl)ethyl]benzenamine.HCl, mp 208°-211°C.

The starting material, 2-chloro-1-[2-(4-nitrophenyl)ethenyl]benzene, isprepared in a manner analogous to Preparations A through K.

PREPARATION 13 4-[2-(2-Methylphenyl)ethyl]benzenamine.HCl, mp 171°-173°C.

The starting material, 2-methyl-1-[2-(4-nitrophenyl)ethenyl]benezene, isprepared in a manner analogous to Preparation A through K.

PREPARATION 14 4-[2-(4-Butoxyphenyl)ethyl]ethylbenzenamine, mp 58°-59°C.

The starting material, 4-butoxy-1-[2-(4-nitrophenyl)ethenyl]benzene, isprepared in a manner analogous to Preparations A through K.

PREPARATION 15 2-[2-(3,4-Dimethoxyphenyl)ethyl]benzenamine, mp 58°-60°C.

The starting material,1,2-dimethoxy-4-[2-(2-nitrophenyl)ethenyl]benzene, is as prepared inPreparation K above.

PREPARATION 16 N-[2-methoxy-5-[(4-aminophenyl)ethyl]phenyl]acetamide, mp135°-140° C.

The starting material,N-[2-methoxy-5-[(4-nitrophenyl)ethyl]phenyl]acetamide, is prepared in amanner analogous to the methods of Preparations A through K.

PREPARATION 17 4-[3-(3,4-dimethoxyphenyl)propyl]benzamine, mp 54°-57° C.

The starting material,1,2-dimethoxy-4-[2-(2-nitrophenyl)propenyl]benzene, is prepared in amanner analogous to Preparations A through K above.

PREPARATION 18 4-[4-(3,4-Dimethoxyphenyl)butyl]benzamide, mp 97°-100° C.

The starting material, 1,2-dimethoxy-[2-(2-nitrophenyl)butenyl]benzeneis prepared in a manner analogous to Preparations A through K above.

B. An alternate method of preparation for a compound of Formula IIIwhereinR₆ is (CH₂)_(n) -R₄ wherein n is 1 or 2 is as follows

PREPARATION 19 4-[(3,4-Dimethoxyphenyl)methyl]aniline (see Scheme III,Formula III₂ Wherein c is two, R₇ is Methoxy and R₅ is Hydrogen)

Mixture of glacial acetic acid (100 ml), 20% Pd/C catalyst (0.5 g) and3,4-dimethoxy-4'-nitrobenzophenone (Tadkod, Kulkarni, and Nargund, J.Karnatak Univ., 3, 78-80 (1958)) (5.4 g, 18.8 mmol) is hydrogenated at52 psi for about five hours.

Concentrated H₂ SO₄ (1.1 ml) and additional 20% Pd/C (0.5 g) are addedand the hydrogenation is continued until five equivalents are consumed(21.2 hours). Potassium acetate (2 g, 20 mmol) is added to the mixtureand the catalyst is removed by filtration through celite. The filtrateis acidified with concentrated HCl (1.7 ml), concentrated in vacuo to aresidual oil and dissolved in 10% HCl (400 ml). The acidic solution iswashed with Et₂ O (2×400 ml) and CH₂ Cl₂ (1×100 ml) and then basifiedwith Na₂ CO₃. The aqueous fraction was extracted with CH₂ Cl₂ and theCH₂ Cl₂ extract was dried with Na₂ SO₄. Evaporation of the volatilesolvent in vacuo gave 4.4 g (96%) of crude oily product whichcrystallizedupon standing. The analytical amine was obtained by columnchromatography; yield, 1.58 g (35%), mp 101°-104°.

An intermediate 4-(3,4-trimethylsilyloxyphenethyl)aniline is prepared inthe following example for use in preparing the compound of Formula IIwherein Q is I₄.

PREPARATION 20 4-(3,4-Trimethylsilyloxyphenethyl)aniline

A mixture of 4-(3,4-dihydroxyphenethyl)aniline (34.39 g, 0.15 mole) andhexamethyldisilazane (24.2 g, 0.15 mole) is heated in a wax bath at120°-160° C. for 3.75 hours under nitrogen, to give dark colored oilyresidue, which is chromatographed on silica gel (160 g). Elution withchloroform gives oily product (47.1 g, 84%) of satisfactory purity forthe next step.

III. Preparation of Compounds of Formula II

PREPARATION I 4H-[1]-Benzothiopyrano[4,3-b]furan-2,3-dione (See SchemeV, Formula XXXII₁ Wherein R₁ is hydrogen)

To a stirred mixture of 4-[trimethyl[silyl]oxy]-2H-benzothiopyran (380.5g,1.609 mol), prepared according to the method of L. Hellberg et al,Tet. Letters, 3553-3554 (1974), and one liter of diethyl ether, wereadded 103.8 g (0.818 mol) of oxalyl chloride in a dropwise manner over aperiod of 50 minutes at room temperature under nitrogen. The mixture wasstirred at room temperature for 17 hours after which time the ether wasremoved under reduced pressure. The residue was triturated withisopropyl ether/hexane to give 146.9 g (82.3%) of a brown crystallinesolid, mp 156° C. (dec).

PREPARATION II 4H-[1]Benzothiopyrano[4,3-b]furan-2,3-dione-S-oxide (SeeScheme V Formula XXII₁ Wherein R₁ is Hydrogen and a=1

A stirred mixture of 4H-[1]benzothiopyrano[4,3-b]furan-2,3-dione (30.48g, 0.139 mol) in 500 ml of dichloromethane was cooled under nitrogen toa temperature between -6° C. and -2° C. A solution of m-chloroperbenzoicacid (24.1 g, 0.139 mol) in 500 ml of dichloromethane was added dropwiseover a period of about 70 minutes. After the addition was complete, themixture was stirred overnight at room temperature. The product,4H-[1]benzothiopyrano-[4,3-b]furan-2,3-dione-S-oxide, was collected byfiltration and washed with isopropyl ether to give 13 g, of material, mp165° C., (dec).

PREPARATION III 4H-[1]Benzothiopyrano(4,3-b]furan-2,3-dione, S,S-dioxide(See Scheme V, Formula XXII₁ Wherein R₁ is Hydrogen and a=2

A stirred mixture of 4H-[1]benzothiopyrano[4,3-b]furan-2,3-dione (26.2,0.12 mol) and 500 ml of dichloromethane was cooled under nitrogen to atemperature between -8° C. and -6° C. A solution of m-chloroperbenzoicacid (48 g, 0.728 mol) in 500 ml of dichloromethane wasadded dropwiseover a period of about 17 minutes. After the addition was complete, themixture was stirred at this temperature for 30 minutes and then at roomtemperature for 19 hours.

The solid which formed was removed by filtration and washed withdichloromethane to yield 28.4 g of m-chlorobenzoic acid. The filtratewas concentrated under reduced pressure and the residual solid wasrecrystallized twice from tetrahydrofuran-isopropyl ether to yield 16.1g (53.6%) of 4H-[1]benzothiopyrano[4,3-b]furan-2,3-dione, S,S-dioxide,as a light yellow crystalline solid, mp 174°-176° C.

PREPARATION IV Benzo[b]thiophene-2-acetic acid;5-chloro-3-hydroxy-α-oxo-methyl ester (See Scheme I, Formula II, Where Qis I₄ wherein R₁ is 5-chloro; y is two; R is methyl)

To a stirred suspension of sodium methoxide (22.34 g, 0.41 mole) inanhydrous ether (1.6 l) under nitrogen at room temperature is addeddimethyl oxalate (48.9 g, 0.41 mole). After 20 minutes the mixture iscooled to 10° C. and a suspension of 5-chloro-3-hydroxybenzo[b]thiophene(L. H. Werner, et al, JACS, 79, 1679 (1957); M. S. ElShanta, et al, J.Chem. Soc., (C)2364 (1967)) (76.4 g, 0.41 mole) in ether (1.45 l) isadded over a period of 30 minutes. After the addition the mixture isstirred at ˜10° C. for three hours and then at room temperature for onehour. After cooling to ˜10° C., cold 4% aqueous sulfuric acid (1 l) isadded and stirred for one hour.

The precipitate is filtered off, washed with water and with ether togive 62.6 g of a solid, mp 185°-6° C. Recrystallization from methylenechloride gives 54.5 g (49.1%) of a light-brown crystalline solid, mp185°-6° C. An additional 4.1 g (3.7%) of product, mp 185°-6° C., isobtained from ether.

Starting materials of Formula XII₆ as shown in Scheme VIII may beprepared as exemplified in the following Preparations V or VI.

PREPARATION V 4-Methyl-2H-furo[3,2-b]indole-3(4H)-one (See Scheme VIII,Formula XII₆Wherein R₁ is hydrogen and R₂ is methyl)

A mixture of 47.0 g (0.18 mole) of3-hydroxy-4-methyl-4H-furo[3,2-b]indole-2-carboxylic ethyl eser (Prep.described in U.S. patent application Ser. No. 369,448) in 450 ml of 95%ethanol was treated with 450 ml of 30% aqueous sodium hydroxide. Themixture was stirred at reflux for two hours, cooled, added to 3.0 kgice/water, and acidified with 6.0N hydrochloric acid. The product wasfiltered, washed with water, and recrystallized from ethanol-water toyield 17.9 g (53% yield) of the product, mp 113°-116° C. An additionalrecrystallization as above raised the mp to 115.5°-118° C.

PREPARATION VI 7-Methoxy-4-phenyl-2H-furo[3,2-b]indole-3(4H)-one (SeeScheme VIII, FormulaXII₆ Wherein R₁ is methoxy, and R₂ is phenyl)

A mixture of 39.0 g (0.12 mole) of3-hydroxy-7-methoxy-4-phenyl-4H-furo[3,2-b]indole-2-carboxylic methylester (Preparation described in U.S. patent application Ser. No. 369,448now issued as U.S. Pat. No. 4,503,236) in 195 ml ofN,N-dimethylformamide and 80 ml of water was treated with 40 ml of 50%aqueous sodium hydroxide,After heating on the steam bath for two hours,the product was isolated as described in Example V above.Recrystallization from 2-methoxyethanol/N,N-dimethylformamide yielded15.8 g (49% yield) of the product, mp 175° C.-dec. An additionalrecrystallization as above raised the mp to 185°-187° C.

IV. Preparation of Compounds of Formula I Wherein Q is I₁

EXAMPLE 1N-[4-[2-(3,4-Dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-α-oxo-2H-1-benzothiopyran-3-acetamide(See Scheme I, Formula I Wherein Q is I₁ Whereina is zero, and b iszero, y is 2, R₅ is hydrogen, and R₆ is 2-(3,4-dihydroxyphenyl)ethyl

A mixture of 4H-[1]benzothiopyrano[4,3-b]furan-2,3-dione, as prepared inPreparation I above (18.6 g, 0.085 mol) and4-[2-(3,4-dihydroxyphenyl)ethyl]benzenamine as prepared in Preparation 7above (17.1 g, 0.0749 mol) in 500 ml of dry tetrahydrofuran was stirredunder nitrogen at room temperature for 18 hours in the dark. The solventwas removed under pressure, and the resulting solid was stirred in 800ml of dichloromethane under reflux for one and one-half hours and thencooledto room temperature.

The resulting precipitate was removed by filtration and washed withdichloromethane to yield 27.8 g of a light yellow solid, mp 165°-166° C.A further crop of 4.9 g of crystals, mp 165°-166° C., was obtained fromthe mother liquor. The two crops were combined and recrystallized fromacetonitrile to yield 28.6 g (85.2%) ofN-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-α-oxo-2H-1-benzothiopyran-3-acetamide,mp 166°-167° C.

EXAMPLE 2N-[4-[2-(3,4-Dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-α-oxo-2H-1-benzothiopyran-3-acetamide,1-oxide (See Scheme I, Formula I Wherein Q is I₁, Wherein a is one, andb is zero; y is two; R₅ is hydrogen; and R₆ is2-(3,4-dihydroxyphenyl)ethyl)

A stirred mixture ofN-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-α-oxo-2H-1-benzothiopyran-3-acetamideas prepared in Example 1 above (17 g, 0.038 mol) in 2.5 liters ofdichloromethane was cooled under nitrogen to a temperature of about -10°C. To this mixture was added dropwise over a period of about 50 minutes,a solution of 13.1 g (0.076 mol) of m-chloroperbenzoic acid in 500 ml ofchloroform. The resulting mixture wasstirred at room temperatureovernight.

The precipitate which formed was removed by filtration, washed withchloroform, and recrystallized from tetrahydrofuran-ethyl acetate toyield15 g (82.4%) ofN-[2-[(3,4-dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-α-oxo-2H-1-benzothiopyran-3-acetamide,1-oxide as a light yellow crystalline solid, mp 185° C. (dec).

EXAMPLE 3N-[4-[2-(3,4-Dimethoxyphenyl)ethyl)phenyl]-4-hydroxy-α-oxo-2H-1-benzothiopyran-3-acetamide,1,1-dioxide (See Scheme I, Formula I Wherein Q is I₁, Wherein a is two,and b is zero; y is two, R₅ is hydrogen; and R₆ is2-(3,4-dimethoxyphenyl)ethyl

A stirred mixture ofN-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-4-hydroxy-α-oxo-2H-1-benzothiopyran-3-acetamideas prepared in Example 1 above (18 g, 0.0393 mol) and 600 ml ofdichloromethane was cooled to a temperature of about -8° C. undernitrogen. To this cooled mixture were added 13.7 g (0.079 mol) ofm-chloroperbenzoic acid in 400 ml of dichloromethane over aperiod ofabout 25 minutes.

The stirred mixture was allowd to slowly warm to room temperature andstirred for an additional 19 hours. The solution was then washedsuccessively with two 1-liter portions of saturated sodium bicarbonatesolution and then a one-liter portion of water. The organic phase wasseparated, dried, and evaporated to yield 18.3 g of a yellow solid, mp180°-181° C.

Recrystallization from tetrahydrofuran-ethanol yielded 14.5 g (72.6%) ofN-[4-[2-(3,4-dimethoxyphenyl)ethyl)phenyl]-4-hydroxy-α-oxo-2H-1-benzothiopyran3-acetamide,1,1-dioxide as light organge crystals, mp 184°-185° C.

In a manner analogous to appropriate Examples 1, 2, or 3 above and usingrespective starting materials the following compounds of Formula IwhereinQ is I₁ and a is zero, one, or two, and y is two are prepared.

EXAMPLE 4N-[4-[2-(4-chlorophenyl)ethyl]phenyl]-4-hydroxy-α-oxo-2H-1-benzothiopyran-3-acetamide,mp 144°-145° C. EXAMPLE 5N-[4-[2-(3,4-Dimethoxyphenyl)ethyl]phenyl]-4-hydroxy-α-oxo-2H-1-benzothiopyran-3-acetamide,mp 146°-148° C. EXAMPLE 6N-[4-[2-(3,4-Dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-α-oxo-2H-1-benzothiopyran-3-acetamide,1,1-dioxide, mp 190° C. (dec) EXAMPLE 7N-[4-[2-(3,4-Dichlorophenyl)ethyl]phenyl]-4-hydroxy-α-oxo-2H-1-benzothiopyran-3-acetamide,mp 172°-173° C. EXAMPLE 8N-[2-[2-(3,4-Dichlorophenyl)ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 180°-2° C. EXAMPLE 9N-(4-Decylphenyl)-4-hydroxy-α-oxo-2H-1-benzothiopyran-3-acetamide,1,1-dioxide, mp 114°-116° C. EXAMPLE 10N-(4-Decylphenyl)-4-hydroxy-α-oxo-2H-1-benzothiopyran-3-acetamide,mp89°-90° C.

Using appropriate starting materials, esters of the Formula II₁ as shownin Scheme V are prepared in a manner analogous to that discussed aboveciting I. W. J. Still and M. T. Thomas. Then the esters are used asshown in Scheme I by Formula II, wherein Q is I₁ ; a is zero, one,ortwo; y is one or two, R₁ is as defined above, and R is lower alkyl toprepare the compound of Formula I wherein Q is I₁ ; a is zero, one, ortwo, y is one or two; R₁, R₅, and R₆ are as defined above depicted byScheme I and exemplified as follows.

EXAMPLE 11N-[4-[2-(3,4-Dichlorophenyl)ethyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide (See Scheme I, Formula I wherein Q is I₁, b is zero, a istwo, y is one, R₅ hydrogen, R₆ is (2-(3,4-dichlorophenyl)ethyl

A mixture of 5.08 g (20 mmol) ofmethyl-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxylate (preparedaccording to the procedure of I. W. J. Still and M. T. Thomas, J. Org.Chem., 33: 2730 (1968)) and 5.32 g (20 mmol) of4-[2-(3,4-dichlorophenyl)ethyl]benzenamine (from Preparation 2 above) in50 ml of xylene were heated at reflux for 18 hours. The yellowprecipitatewhich formed upon cooling the reaction mixture was collectedby filtration to give 6.28 g (64%) of material melting at 238°-242° C.Onerecrystallization from acetone gave 5.08 g (52% ) ofN-[4-[2-(3,4-Dichlorophenyl)ethyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 234°-236° C.

EXAMPLE 124-[2-[4-[[(3,4-Dihydro-4-oxo-2H-1-benzothiopyran-3-yl)carbonyl]amino]phenyl]ethyl]benzoicacid, 1,1-dioxide (See Scheme I, Formula I wherein Q is I₁, R₁ ishydrogen, b is one, a is two, y is one, R₅ is hydrogen, and R₆ is2-(4-carboxylphenyl)ethyl

A mixture of4-[2-[4-[[(3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-yl)carbonyl]amino]phenyl]ethyl]benzoic,ethyl ester, 1,1-dioxide (2 g, 4.1 mmol, from a following Example 47)and 100 ml of 5% sodium hydroxide solution was stirred and heated underreflux for one-half hour. The solution was cooled, acidified withconcentrated hydrochloric acid to pH 2, and the solid which precipitatedwas collected by filtration. The crude product was recrystallized frommethanol to yield 0.5 g of pure4-[2-[4-[[(3,4-Dihydro-4-oxo-2H-1-benzothiopyran-3-yl)carbonyl]amino]phenyl]ethyl]benzoicacid, 1,1-dioxide, mp 256259° C.

EXAMPLE 13N-[4-[2-[3,4-Bis(acetyloxy)phenyl]ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide (See Scheme I, Formula I Wherein Q is I₁, Wherein a is two,b is zero, y is one, R₅ is hydrogen and R₆ is2-[3,4-bis(acetyloxy)phenyl]ethyl)

A mixture of 19.6 g (43 mmol) ofN-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, 120 ml of 10% sodium hydroxide, and 423 mmol of aceticanhydride was stirred for 20 minutes at room temperature. Theprecipitate which formed was collected and washed successively withwater, 5% sodium bicarbonate solution, and again with water, and thendried. The orange-brown material was recrystallized from acetonitrile toyield 10.4 g (45%) ofN-[4-[2-[3,4-Bis(acetyloxy)phenyl]ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 214°-215° C.

EXAMPLE 14N-[4-[(3,4-Dihydroxyphenyl)methyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide (See Scheme I, Formula I wherein Q is I₁, Wherein a is two,b is zero, y is one, R₅ is hydrogen; R₆ is (3,4-dihydroxyphenyl)methyl

A suspension of 1.0 g (2.1 mmol) ofN-[4-[(3,4-dimethoxyphenyl)methyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide and BBr₃.S (CH₃)₂ (4.0 g, 12.6 mmol) in 150 ml ofdichloromethane was heated under reflux under nitrogen for 18 hours. Theresulting yellow suspension was poured onto 600ml of ice water, stirredfor one and one-half hours and then filtered. The crude product wasrecrystallized from isopropanol-water to yield 544 mg (59%) ofN-[4-[(3,4-dihydroxyphenyl)methyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 216°-218° C.

In a manner analogous to that found in Examples 11-12 using appropriatestarting materials the following compounds are also prepared.

EXAMPLE 153,4-Dihydro-4-oxo-N-[(4-(phenyl)methyl]phenyl]-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 193°-196° C. (Enol form of Example 24) EXAMPLE 163,4-Dihydro-4-oxo-N-[(4-(2-phenyl)ethyl]-phenyl]-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 210°-212° C. EXAMPLE 17N-[4-[(3,4-Dimethoxyphenyl)methyl]phenyl]-3,4-dihydro-4-oxo-2H-benzothiopyran-3-carboxamide,1,1-dioxide, mp 170°-172° C. EXAMPLE 18N-[4-[2-(3,4-Dimethoxyphenyl)ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 191°-193° C. EXAMPLE 19N-[4-[3-(3,4-Dimethoxyphenyl)propyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 165°-166° C. EXAMPLE 20N-[4-[4-(3,4-Dimethoxyphenyl)butyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 184°-185° C. EXAMPLE 21N-[4-[2-(3,4-Dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide, 1,1-dioxide, mp 218 (dec) (Enol form of Example 24)EXAMPLE 22N-[4-[3-(3,4-Dihydroxyphenyl)propyl]phenyl]-3,4-dihydro-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 171°-173° C. EXAMPLE 23N-[4-[4-(3,4-Dihydroxyphenyl)butyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 196°-199° C. EXAMPLE 24N-[4-[2-(3,4-Dihydroxyphenyl)ethyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 218° C. (Keto form of Example 21) EXAMPLE 25N-[4-[2-(3,4-Dimethoxyphenyl)ethyl]phenyl]-4-hydroxy-6-methoxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 222°-223° C. EXAMPLE 266-Chloro-N-[4-[2-(3,4-dimethoxyphenyl)ethyl]-phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 210°-213° C. EXAMPLE 27 3,4-Dihydro-N-[4-[2-(3-hydroxy-4-methoxyphenyl)ethyl]phenyl]-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 230°-233° C. EXAMPLE 28N-[4-[2-(2,3-Dimethoxyphenyl)ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 188°-190° C. EXAMPLE 29N-[4-[2-(2,3-Dihydroxyphenyl)ethyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 200°-202° C. EXAMPLE 30N-[4-[2-(2,4-Dimethoxyphenyl)ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 195°-198° C. EXAMPLE 31N-[4-[2-(2,4-Dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 205°-208° C. EXAMPLE 32N-[4-[2-(2,5-Dimethoxyphenyl)ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 180°-181° C. EXAMPLE 33N-[4-[2-(3,5-Dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide, 1,1-dioxide, mp 237° C. (dec) EXAMPLE 34N-[4-[2-(3,5-Dimethoxyphenyl)ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 201-202 EXAMPLE 354-Hydroxy-N-[4-[2-(3,4,5-trimethoxyphenyl)ethyl]phenyl-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 175°-177° C. EXAMPLE 364-Hydroxy-N-[4-[2-(3,4,5-trihydroxyphenyl)ethyl]phenyl-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 152° C. (dec) EXAMPLE 37 4-Hydroxy-N-84-[2-(2-methoxyphenyl)ethyl]phenyl-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 189°-191° C. EXAMPLE 384-Hydroxy-N-[4-[2-(2-hydroxyphenyl)ethyl]phenyl-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 219°-220° C. EXAMPLE 393,4-Dihydro-N-[4-[2-(3-methoxyphenyl)ethyl]phenyl-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 189°- 190° C. EXAMPLE 403,4-Dihydro-N-[4-[2-(4-hydroxyphenyl)ethyl]phenyl-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 235°-237° C. EXAMPLE 413,4-Dihydro-N-[4-[2-(4-methoxyphenyl)ethyl]phenyl-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 223°-225° C. EXAMPLE 42N-[4-[2-(2-Chlorophenyl)ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 226°-229° C. EXAMPLE 434-Hydroxy-N-[4-[2-(2-methylphenyl)ethyl]phenyl-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 209°-211° C. EXAMPLE 443,4-Dihydro-4-oxo-N-[4-[2-(4-(trifluoromethyl)phenyl)ethyl]phenyl-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 223°-224° C. EXAMPLE 453,4-Dihydro-N-[4-[2-(4-methylphenyl)ethyl]phenyl-4-oxo-2H-1-benzothiopyran-3-carboxamide, 1,1-dioxide, mp 213°-216° C. EXAMPLE 46N-[4-[2-([1,1'-biphenyl]-4-yl)ethyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 248°-252° C. EXAMPLE 474-[2-[4-[[(3,4-Dihydro-4-oxo-2H-1-benzothiopyran-3-yl)carbonyl]amino]pheyl]ethyl]benzoicacid, ethyl ester, 1,1-dioxide, 213°-215° C. EXAMPLE 48N-[4-[2-(4-Butoxyphenyl)ethyl]phenyl-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 185°-187° C. EXAMPLE 49N-[4-[2-(4-(Acetylamino)phenylethyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 256°-258° C. EXAMPLE 50N-[4-[2-(3-Acetylamino-4-methoxy)ethyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 255°-258° C. EXAMPLE 514-Hydroxy-N-[4-[2-(2-naphthalenyl)ethyl]phenyl]-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 222°-225° C. EXAMPLE 52N-[4-[2-(4-Aminophenyl)ethyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 210°-245° C. EXAMPLE 53N-[4-[2-(3,4-Dimethylphenyl)ethyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 207°-209° C. EXAMPLE 54N-[4-[2-(4-Chlorophenyl)ethyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 242-245 EXAMPLE 55N-[4-[2-[4-(Dimethylaminophenyl)ethyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide.HCl, mp 234°-237° C. EXAMPLE 56N-[2-[2-(3,4-Dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 195°-210° C. EXAMPLE 57N-[2-[2-[3,4-Dimethoxyphenyl)ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide, 1,1-dioxide, mp 192°-196°C. EXAMPLE58N-(4-Hexylphenyl)-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1-1-dioxide, mp 169.5°-170° C. EXAMPLE 593,4-Dihydro-N-(4-octylphenyl)-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 169°-170° C. EXAMPLE 60N-(4-Decylphenyl)-3,4-dihydro-4-oxo-2H-1-benzoothiopyran-3-carboxamide,1,1-dioxide, mp 156°-158° C. EXAMPLE 61N-(4-Dodecylphenyl)-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 156°-158° C. EXAMPLE 62N-[4-[2-(3-Trifluoromethylphenyl)ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 188°-195° C. EXAMPLE 63N-[4-[2-[3,5-bis-Trifluoromethyl(phenyl)]ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, mp 232°-234° C. EXAMPLE 64N-[4-[2-(2,3,4,5,6-Pentafluorophenyl)ethyl]phenyl]-4-hydroxy-2H-1-benzothiopyran-3-carboxamide,1,1-dioxide, 216°-218° C. EXAMPLE 65N-[4-[2-(3,4-Dihydroxyphenyl)ethyl]phenyl]-4,6-dihydroxy-2H-benzothiopyran-3-carboxamide,1,1-dioxide, mp 234°-235° C. EXAMPLE 662H-1-Benzothiopyran-3-carboxamide,N-[4-[2-(4-aminophenyl)ethenyl]phenyl]-3,4-dihydro-4-oxo-, 1,1-dioxide,mp>300 C. EXAMPLE 67 2H-1-Benzothiopyran-3-carboxamide,3,4-dihydro-N-[4-[2-(4-nitrophenyl)ethenyl]phenyl]-4-oxo-, 1,1-dixide,mp 262°-266° C. EXAMPLE 68 2H-1-Benzothiopyran-3-carboxamide,N-[4-[2-(3-chlorophenyl)ethyl]phenyl]-4-hydroxy-, 1,1-dioxide, mp195°-197° C. EXAMPLE 69 2H-1-Benzothiopyran-3-acetamide,N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl]-4-hydroxy-α-oxo-, 1,1-dioxide,mp 197° C. (dec) EXAMPLE 70 2H-1-Benzothiopyran-3-carboxamide,4-hydroxy-N-[4-[2-(4-hydroxy-3-methoxyphenyl)ethyl]phenyl]-,1,1-dioxide, mp 225°-228° C. EXAMPLE 712H-1-Benzothiopyran-3-carboxamide,N-[4-[2-(3,5-dichlorophenyl)ethyl]phenyl]-4-hydroxy-, 1,1-dioxide, mp206°-210° C. EXAMPLE 72 2H-1-Benzothiopyran-3-carboxamide,N-[4-[2-(2,4-dichlorophenyl)ethyl]phenyl]-4-hydroxy-1,1-dioxide, mp227°-32° C. EXAMPLE 73 2H-1-Benzothiopyran-3-carboxamide,4-hydroxy-N-[4-[2-(1-naphthalenyl)ethyl]phenyl], 1,1-dioxide, mp214°-5-°C. EXAMPLE 74 2H-1-Benzothiopyran-3-carboxamide,N-[4-[2-(3,4-dichlorophenyl)ethenyl]phenyl]-4-hydroxy-, 1,1-dioxide, mp264°-268° C. EXAMPLE 75 2H-1-Benzothiopyran-3-carboxamide,4-hydroxy-N-[4-[ 2-(4-phenoxyphenyl)ethyl]phenyl]-, 1,1-dioxide, mp168°-72° C. EXAMPLE 76 2H-1-Benzothiopyran-3-carboxamide,N-[3-[2-(3,4-dichlorophenyl)ethyl]phenyl]-4-hydroxy-, 1,1-dioxide, mp181°-183° C. EXAMPLE 77 2H-1-Benzothiopyran-3-carboxamide,N-[4-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethyl]phenyl]-4-hydroxy-,1,1-dioxide, mp 213°-5° C. EXAMPLE 78 2H-1-Benzothiopyran-3-carboxamide,N-[4-[(3,4-dichlorophenyl)methyl]phenyl]-4-hydroxy-, 1,1-dioxide, mp203°-200° C. EXAMPLE 79 2H-1-Benzothiopyran-3-carboxamide,N-[4-[3-(3,4-dichlorphenyl)propyl]phenyl]-4-hydroxy-, 1,1-dioxide, mp168°-170° C. EXAMPLE 80 2H-1-Benzothiopyran-3-carboxamide,N-[2-[3-(3,4-dichlorophenyl)propyl]phenyl]-4-hydroxy-, 1,1-dioxide, mp180°-182° C. EXAMPLE 81 2H-1-Benzothiopyran-3-carboxamide, N-[2-[(3,4-dichlorophenyl)methyl]phenyl]-4-hydroxy, 1,1-dioxide, mp205°-207° C. EXAMPLE 82 2H-1-Benzothiopyran-3-carboxamide,3,4-dihydro-N-[4-[2-(3-hydroxyphenyl)ethyl]phenyl-4-oxo, 1,1-dioxide, mp224°-225° C.

V. Preparation of Compounds of Formula I Wherein Q is I₂

Compounds of Formula II wherein Q is I₂ are prepared in accordance withthe conditions detailed in U.S. Pat. No. 3,591,584 cited above and usedas shown in Scheme I to prepare the compounds of Formula I wherein Q isI₂. Representative examples are as follows.

EXAMPLE 83N-[4-[2-(3,4-Dimethoxyphenyl)ethyl)phenyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide,1,1-dioxide (See Scheme I, Formula I Wherein Q is I₂ Wherein b is zero,Y is 1, R₅ is H; Z is methyl, R₆ is 2-(3,4-dimethoxyphenyl)ethyl)

A mixture of methyl4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (J. D.Genzer and F. C. Fontsere, U.S. Pat. No. 3,960,856 (1976)) (5.9 g, 0.022mole) and 4-[2-(3,4-dimethoxyphenylethyl]benzenamine(5.6 g, 0.022 mole)in xylene (600 ml) is heated at reflux for 24 hours in a soxhletapparatus, the thimble of which contains 20 g of Linde type 4A molecularsieve. The reaction mixture is allowed to cool when the productcrystallized out. The product is filtered, washed with methanol, anddriedto give 9.8 g of white crystals, mp 235°-8° C.

In a manner analogous to that found in Example 83 above usingappropriate starting materials additional compounds are prepared asfollows.

EXAMPLE 84N-[4-[2-(3,4-dimethoxyphenyl)ethyl)phenyl]-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide,1,1-dioxide, mp 201°-205° C. EXAMPLE 85N-[2-[2-(3,4-dimethoxyphenyl)ethyl)phenyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide,1,1-dioxide, mp 130°-135° C. EXAMPLE 86N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide,1,1-dioxide, mp 260°-262° C. EXAMPLE 872H-1,2-Benzothiazine-3-carboxamide,4-hydroxy-N-[4-[2-(4-hydroxy-3-methoxyphenyl)ethenyl]phenyl]-2-methyl,1,1-dioxide, mp 257°-259° C. EXAMPLE 882H-1,2-Benzothiazine-3-carboxamide,4-hydroxy-N-[4-[2-(4-hydroxy-3-methoxyphenyl)ethyl]phenyl]-2-methyl-,1,1-dioxide, mp 231°-231.5° C. EXAMPLE 89N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide,1,1-dioxide (see Scheme I, Formula I Wherein Q is I₂, Wherein b is zero,Z is Methyl, R₅ is hydrogen, R₆ is 2-(3,4-dihydroxyphenyl)ethyl)

A cold (0°-10° C.) mixture ofN-[4-[2-(3,4-dimethoxyphenyl)ethyl)phenyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide,1,1-dioxide (19.8 g, 0.04 mole) and methylene chloride (1000 ml) istreated slowly with boron tribromide (100 g; 0.4 mole) during 30minutes. The yellow-green solution is allowed to warm up to roomtemperature when a precipitate is formed. The reaction mixture isstirred at room temperature for 4.5 hours and then slowly poured into 30lof ice water and stirred for 45 minutes. The precipitated solid isfiltered, washed with water, and dried. The crude product is thentriturated with hot methanol and filtered to give a white solid (15.6 g;83%), mp 257°-9° C. dec.

In a manner analogous to that found in Example 86 above usingappropriate starting materials an additional compound is prepared asfollows.

EXAMPLE 90N-[2-[2-(3,4-Dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide,1,1-dioxide, mp 178°-180° C.

VI. Preparation of Compounds of Formula I Wherein Q is I₃

A. Intermediates of Formula XII and XXIII.

Intermediates of the Formula XIII or XXIII as shown in Scheme VI to beuseful in the preparation of compounds of Formula I wherein Q is I₃ areprepared from the compounds of Formula III in a manner shown in SchemeXand exemplified as follows.

EXAMPLE 91 N'-[4-[2-(3,4-Dimethoxyphenyl)ethyl]phenyl-N,N-diphenyl urea(see Formula XIII in Scheme VI Wherein R₅ is hydrogen and R₆ is4-[2-(3,4-dimethoxyl phenyl)ethyl])

A mixture of 30.0 g (0.12 mole) of4-[2-(3,4-dimethoxyphenyl)ethyl]benzenamine (as prepared in Preparation1 above), 24.7 g (34 ml, 0.24 mole) of triethylamine, and 27.0 g (0.12mole)of diphenylcarbamyl chloride in 180 ml of absolute ethanol wasstirred at reflux for 17 hours. The cooled reaction mixture wasevaporated, and the residue was partitioned between dichloromethane (600ml) and water (400 ml). The organic layer was washed with 1Nhydrochloric acid (3×400 ml), brine (1×400 ml), dried (sodium sulfate),and evaporated. Recrystallization of the residue from ethylacetate/hexane yielded 44.9 g (82% yield) of the urea product, mp113°-115° C.

EXAMPLE 92 N-[4-[2-(4-Methoxyphenyl)ethyl]phenyl-N,N-diphenyl urea (SeeScheme VI, Formula XIII Wherein R₅ is hydrogen and R₆ is4-[2-(4-methoxyphenyl)ethyl]

A mixture of 60.0 g (0.26 mole) of4-[2-(4-methoxyphenyl)ethyl]benzenamine (L. A. Strait, D. Jambotkar, R.Ketcham, and M. Hrenoff, J. Org. Chem., 31, 3976 (1966)), 55.7 g (77 ml;0.55 mole) of triethylamine, and 61.2 g (0.26 mole) of diphenylcarbamylchloride in 380 ml of absolute ethanol wasstirred at reflux for 24hours. The reaction mixture was cooled and the precipitated solid wasfiltered and washed with water. Recrystallization from ethanol yielded96.4 g (86% yield) of the urea product, mp 121°-124° C.

EXAMPLE 93 N'-(4-Decylphenyl)-N,N-diphenyl urea (see Scheme VI, FormulaXIII Wherein R₅ is hydrogen and R₆ is 4-decylphenyl)

Prepared by the procedure described in Example 92 above from 5.0 g(0.021 mole) of 4-decylbenzenamine. Recrystallization from methanolyielded 7.1 g(77% yield) of the urea product, mp 90°-91° C.

EXAMPLE 94 N'-(4-Dodecylphenyl)-N,N-diphenyl urea (See Scheme VI,Formula XIII WhereinR₅ is hydrogen and R₆ is 4-dodecylbenzenamine)

Prepared by the procedure described in Example 92 from 5.0 g (0.019mole) of 4-dodecylbenzeamine. Recrystallization from methanol yielded6.7 g (77%yield) of the urea product, mp 92°-94° C.

EXAMPLE 95 N'-[4-[2-(3,4-Dichlorophenyl)ethyl]phenyl-N,N-diphenyl urea(See Scheme VI,Formula XIII Wherein R₅ is hydrogen and R₆ is4-[2-(3,4-dichlorophenyl)ethyl])

Prepared by the procedure described in Example 92 from 3.0 g (0.011mole) of 4-[2-(3,4-dichlorophenyl)ethyl]benzenamine. There was obtained4.5 g (86%) of the urea product, mp 153°-155° C.

EXAMPLE 96 N'-[4-[2-(4-Chlorophenyl)ethyl]phenyl-N,N-diphenyl urea (SeeScheme VI, Formula XIII Wherein R is hydrogen and R₆ is4-[2-(4-chlorophenyl)ethyl])

Prepared by the procedure described in Example 92 from 3.0 g (0.013mole) of 4-[2-(4-chlorophenyl)ethyl]benzenamine (Chem. Abstrs., 93,63,603q (1980)). Recrystallization from methanol yielded (54% yield) ofthe urea product, mp 180°-182° C.

EXAMPLE 97 [4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino]-oxoacetic acidethyl ester (See Scheme VI, Formula XXIII Wherein R₅ is hydrogen and R₆is 4-[2-(3,4-dichlorophenyl)ethyl])

A mixture of 32.9 g (0.12 mole) of4-[2-(3,4-dichlorophenyl)ethyl]benzeamine, and 22.5 g (31 ml, 0.22 mole)of triethylamine in 75 ml of N,N-dimethylformamide was cooled in ice andtreated over 20 minutes with 21.4 g (17.5 ml, 0.16 mole) of ethyl oxalylchloride. After one hour, the ice bath was removed, and the mixture wasstirred for an additional 24 hours. The reaction mixture was added to1.0 kg ice/water, and the precipitated solid was filtered and washedwith water. Recrystallization from methanol/N,N-dimethylformamide/wateryielded41.3 g (91% yield) of the amide product, mp 128°-130° C.

EXAMPLE 98 [(4-Decylphenyl)amino]-oxo-acetic acid ethyl ester (SeeScheme VI, Formula XIII Wherein R₅ is hydrogen and R₆ is 4-decyphenyl

Prepared by the procedure described in Example 99 from4-decylbenzenamine (9.3 g, 0.040 mole). Recrystallization frommethanol/water yielded 10.2 g (77% yield) of the amide product, mp56°-58° C.

EXAMPLE 99 [4-[2-(3,4-Dimethoxyphenyl)ethyl]phenylamino]-oxoacetic acidethyl ester (See Scheme VI, Formula XXIII Wherein R₅ is hydrogen and R₆is 4-[2-(3,4-dimethoxyphenyl)ethyl]

Prepared by the procedure described in Example 97 from4-[2-(3,4-dimethoxyphenyl)ethyl]benzenamine (15.3 g, 0.059 mole).Recrystallization from methanol water yielded 18.6 g (88% yield) of theamide product, mp 122°-124° C.

B. Compounds of Formula I Wherein Q is I₃

For compounds of Formula I having Q equal to I₃ the preparation is shownin Scheme VI where the compounds of Formula XII₃ are reacted with XIIIor XXIII. The preparation is exemplified as follows.

EXAMPLE 100 2-Benzofurancarboxamide,N-[4-[2-(3,4-Dimethoxyphenyl)ethyl]phenyl]-2,3-dihydro-7-methoxy-3-oxo-(SeeScheme VI, Formula I wherein y is one, Q is I₃, Wherein R₁ is 7-methoxy,b is one, R₅ is hydrogen, and R₆ is 4-[2-(3,4-dimethoxyphenyl)ethyl]

A mixture of 1.8 g (0.038 mole) of 50% sodium hydride mineral oilsuspension in 100 ml of N,N-dimethylformamide under a nitrogenatmosphere was stirred and cooled in ice. To the mixture was added over30 minutes, 5.5 g (0.034 mole) of 7-methoxy-3-[2H]-benzofuranone. Afterstirring for an additional one hour, 15.8 g (0.037 mole) ofN'-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl-N,N-diphenyl urea as preparedin Example 91 above was added, and the ice bath was removed. The mixturewas stirred for 48 hours, added to 700 g ice/water, and acidified withacetic acid. The precipitated solid was filtered, washed with water, andrecrystallized from 2-methoxyethanol/water to yield 9.1 g (61% yield) ofthe amide product, mp 173°-175° C.

In a manner analogous to the above Example 100 using appropriatestarting materials the following compounds are prepared.

EXAMPLE 101 Naphtho[2,3-b]furan-2-carboxamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-2,3-dihydroxy-3-oxo, mp220°-223° C. EXAMPLE 102 2-Benzofurancarboxamide,N-[4-[2-(3,4-dimethoxyphenyl)ethylphenyl)-3-hydroxy, mp 175°-176° C.EXAMPLE 103 Naptho[2,1-b]furan-2-carboxamide,1-hydroxy-N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl], mp 176°-179° C.EXAMPLE 104 Naphtho[2,3-b]furan-2-carboxamide,N-(4-dodecylphenyl)-3-hydroxy, mp 182°-184° C. EXAMPLE 1052-Benzofurancarboxamide, N-(4-dodecylphenyl)-3-hydroxy mp 154°-156° C.EXAMPLE 106 Naphtho[1,2-b]furan-2-carboxamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-2,3-dihydro-3-oxo, mp172°-174° C. EXAMPLE 107 2-Benzofurancarboxamide,N-(4-decylphenyl)-3-hydroxy, mp 161°-162° C. EXAMPLE 108Naphtho[2,3-b]furan-2-carboxamide, N-(4-decylphenyl)-3-hydroxy, mp185°-188° C. EXAMPLE 109 Naptho[2,1-b]furan-2-carboxamide,N-[4-[2-(3,4-dimethylphenyl)ethyl]phenyl]-1-hydroxy

A mixture of 1.88 g (2.6 ml, 0.019 mole) of diisopropylamine in 20 mloftetrahydrofuran under a nitrogen atmosphere was cooled to 0° to -10° C.in an ice/sodium chloride cooling bath. The mixture was stirred andtreated over 20 minutes with a solution of 8.8 ml (0.019 mole)of n-butyllithium (2.1M in n-hexane) at a rate that allowed the reaction mixtureto remain at <0° C. The mixture was stirred for an additional 20minutes, and then a solution of 1.95 g (0.087 mole) of4-[2-(3,4-dimethylphenyl)ethyl]benzenamine in 20 ml of tetrahydrofuranwasadded over 15 minutes. After stirring for an additional 20 minutes, asolution of 2.0 g (0.083 mole) of1,2-dihydro-1-oxo-naphtho[2,1-b]furan-2-carboxylic acid methyl ester(preparation for the isomeric naphtho[2,3-b]furan ester described by P.Emmott and R. Livingstone, J. Chem. Soc., 4629 (1958)) in 20 ml oftetrahydrofuran was added over 20 minutes. The mixture was stirred asthe cooling bath was allowed to slowly melt over 18 hours. The reactionmixture was added to 600 g of ice water containing 8.0 ml ofconcentrated hydrochloric acid. After stirring for two hours, theprecipitated solid was filtered, washed with water, and recrystallizedfrom 2-propanol/N,N-dimethylformamide/water to yield 1.0 g (28% yield)of the amide product, mp 188°-191° C.

In a manner analogous to that described above in Example 109 there wasalsoprepared:

EXAMPLE 110 Naphtho[2,1-b]furan-2-carboxamide,N-[4-[2-(4-hydroxy-3-methoxyphenyl)ethyl]phenyl]-1,2-dihydro-1-oxo, mp189°-191° C.

By employing 4-[2-(4-hydroxy-3-methoxyphenyl)ethyl]benzenamine as theamine, plus an additional equivalent amount of diisopropylamine andn-butyl lithium in order to complex with the amine hydroxyl group duringreaction.

EXAMPLE 111 2-Benzofuranacetamide,N-[4-[2-(3,4-Dimethoxyphenyl)ethyl]phenyl]-2,3-dihydro-7-methoxy-α,3-dioxo-(SeeScheme VI, Formula I Wherein y is 2, Q is I₃ ; Wherein b is one, R₁ is7-methoxy, R₅ is hydrogen, and R₆ is 4-[2-(3,4-dimethoxyphenyl]ethyl])

Prepared by the procedure described in Example 109 from 6.3 g (0.038mole) of 7-methoxy-3[2H]-benzofuranone, except that[4-[2-(3,4-dimethoxyphenyl)ethyl]phenylamino]-oxo-acetic acid ethylester (15.1 g, 0.042 mole) was employed as the acylating agent ratherthan the mixed urea used in Example 109. Recrystallization of the finalproduct from N,N-dimethylformamide/water yielded 7.5 g (41% yield) ofthe amide product, mp 242°-245° C.

In a manner analogous to Example 111 above using appropriate startingmaterials the following compounds are prepared.

EXAMPLE 112 Naphtho[2,1-b]furan-2-acetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-1-hydroxy-α-oxo, mp 229°-230°C. EXAMPLE 113 Naphtho[2,3-b]furan-2-acetamide,N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl]-3-hydroxy-α-oxo, mp 271°-273°C. EXAMPLE 114 Naphtho[1,2-b]furan-2-acetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-α-oxo, mp 225°-231°C. EXAMPLE 115 2-Benzofuranacetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-5,6-dimethoxy-α-oxo,mp 248°-250° C. EXAMPLE 116 2-Benzofuranacetamide,N-(4-decylphenyl)-2,3-dihydro-α,3-dioxo, mp 175°-178° C. EXAMPLE 117Naptho[2,3-b]furan-2-acetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-2,3-dihydro-α,3-dioxo,mp244°-246° C. EXAMPLE 118 2-Benzofuranacetamide,N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl-2,3-dihydro-α,3-dioxo, 245° C.dec EXAMPLE 119 2-Benzofuranacetamide,N-[4-decylphenyl]-3-hydroxy-5,6-dimethoxy-α-oxo, mp 187°-188° C. EXAMPLE120 Naphtho[2,3-b]furan-2-acetamide,N-[4-decylphenyl]-2,3-dihydro-α,3-dioxo, mp 218°-221° C. EXAMPLE 1212-Benzofuranacetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-α-oxo, mp 238°-240°C.

Ether cleavage to obtain compounds corresponding to hydroxy bearingcompounds are exemplified hereafter.

EXAMPLE 122 Naphtho[2,1-b]furan-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-1-hydroxy-

A mixture of 19.5 g (0.062 mole) of boron tribromide dimethyl sulfidecomplex in 300 ml of 1,2-dichloroethane under a nitrogen atmosphere, wascooled in ice and treated with 6.0 g (0.013 mole) ofN-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-1-hydroxynaphtho[2,1-b]furan-2-carboxamideas prepared in Example 103 above. The mixture was stirred at reflux for18 hours, cooled, and added to 1.0 kg ice/water. After stirringforseveral hours, the emulsion was extracted with ethyl acetate (3×750 ml),and the organic layers were combined, dried (sodium sulfate), andevaporated. Recrystallization of the residue frommethanol/N,N-dimethylformamide/water yielded 2.5 g (44% yield) of thecatechol product, mp 214°-216° C.

In a manner analogous to Example 122 above using appropriate startingmaterials the following compounds are prepared.

EXAMPLE 123 2-Benzofuranacetamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-7-methoxy-α-oxo,0.25 H₂ O, mp 260° C. dec EXAMPLE 124 2-Benzofurancarboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy, mp 208°-209° C.EXAMPLE 125 Naphtho[1,2-b]furan-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy, 0.5 H₂ O, mp180°-185° C. EXAMPLE 126 2-Benzofuranacetamide,N-[4-[2-(3,4-Dihydroxyphenyl)ethyl]phenyl]-2,3-dihydro-α,3-dioxo- (SeeScheme VI, Formula I Wherein y is 2; Q if I₃ Wherein R₁ is Hydrogen; R₅is Hydrogen; R₆ is 4-[2-(3,4-dihydroxyphenyl)ethyl]

A mixture of 4.3 g (0.0097 mole) ofN-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-α-oxo-2-benzofuranacetamideas prepared in Examples 121 above in 250 ml of dichloromethaneunder anitrogen atmosphere was cooled to -78° C. To the mixture wasadded 46 ml(0.046 mole) of 1.0M solution of boron tribromide in dichloromethane.The mixture was stirred for four hours at -78° C.,and then for 22 hourswith the cooling bath removed. The mixture was recooled to -10° C. and200 ml of cold water was added. After stirring for several hours, theinsoluble material was filtered and washedwith water. The crude productwas digested on the steam bath for 90 minutesin 800 ml of 50% aqueousmethanol. The mixture was cooled and the insolublematerial againfiltered and washed with water. Recrystallization fromtetrahydrofuran/ethanol yielded 2.3 g (58% yield) of the catecholproduct,mp 231°-232° C.

In a manner analogous to above Example 126 using appropriate startingmaterials the following compounds are prepared.

EXAMPLE 127 2-Benzofuranacetamide,N-(4-decylphenyl)-3,5,6-trihydroxy-α-oxo, 278°-280° C. dec EXAMPLE 128Naphtho[2,3-b]furan-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy, 1H₂ O, mp165°-169° C. EXAMPLE 129 Naphtho[2,3-b]furan-2-acetamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]-2,3-dihydro-α,3-dioxo, 0.2H₂ O, mp278°-281° C. EXAMPLE 130 2-Benzofuranacetamide,N-[4-[2-(3,4-Dihydroxyphenyl)ethyl]phenyl]-3,5,6-trihydroxy-α-oxo, mp282°-284° C. dec

VII. Preparation of Compounds of Formula I Wherein Q is I₄

For compounds of Formula I wherein Q is equal to I₄ the preparationasshown in Scheme I is examplified as follows.

EXAMPLE 131N-[4-[2-(3,4-Dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-α-oxo-benzo[b]thiophene-2-acetamide(See Scheme I, Formula I, Wherein Q is I₄, Whereinb is zero; y is 2; R₅is hydrogen; R₆ is 4-[2-(3,4-dimethoxyphenyl)ethyl])

To a stirred solution of benzo[b]thiophene-2-acetic acid,3-hydroxy-α-oxo (Fries and Bartholomaus, Annalen, 405, 391 (1914))(44.44 g, 0.2 mole) and 4-(3,4-dimethoxyphenethyl)aniline (51.46 g, 0.2mole) in methylene chloride (2.5 l) and tetrahydrofuran (1 l) undernitrogen at -7° C. is added a solution of dicyclohexycarbodiimide (41.7g, 0.202 mole) in methylene chloride (200 ml) over a period of 55minutes. The mixture is stirred at -7° to 0° C. for two hours and atroom temperature overnight. The precipitate is collected by filtrationand washed with methylene chloride to give a solid, consisting of theproduct and dicyclohexylurea. Evaporation of the mother liquor underreduced pressure below 45° C. gives a solid, which is combined with thefirst crop, dissolved in ˜4 1 of boiling chloroform and left at roomtemperature overnight. Dicyclohexylurea (26 g)is removed by filtrationand the filtrate is chromatographed on 1 kg of silica gel. Elution withchloroform gives 61.4 g of a solid. Recrystallization fromtetrahydrofuran yields 53.2 g (57.6%) of a light-yellow crystallinesolid, mp 204°-205° C.

EXAMPLE 132N-[4-[2-(3,4-Dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-α-oxo-benzo[b]thiophene-2-acetamide(Alternate preparation of the same compound as in Example 131)

To a stirred solution of diisopropylamine (3.3 g, 0.03 mole) in drytetrahydrofuran (20 ml) cooled to 0° C. is added streamwise undernitrogen n-butyllithium (13.05 ml, 0.03 mole; 2.3M solution of n-butyllithium in hexane). After the addition the solution is allowed to stirat ice bath temperature for 15 minutes and then a solution of4-(3,4-dimethoxyphenethyl)aniline (3.08 g, 0.012 mole) intetrahydrofuran (30 ml) is added. The greenish colored solution isstirred in an ice bath for 18 minutes and a solution ofbenzo[b]thiophene-2-acetic acid-3-hydroxy-α-oxo-methylester (Bo Lamm andCarl-Johan Aurell, Acta Chemica Scandinavica, Ser. B., 36(7), 435-42(1982)) (2.36 g, 0.01 mole) in tetrahydrofuran (35 ml) is added. Theyellow colored solution is stirred at ice bath temperature for 15minutes and then at room temperature for one hour. The mixture is pouredinto 10% aqueous hydrochloric acid (300 ml) and the solid is filteredoff, washed with hydrochloric acid (˜200 ml), with water, and dried togive 4.5 g (90.2%) of a solid, mp 203°-04° C.

Recrystallization from tetrahydrofuran gives 3.2 (69.6%) of alight-yellow crystalline solid, mp 204°-205° C.

EXAMPLE 133N-[4-[2-(3,4-Dihydroxyphenyl)ethyl]-3-hydroxy-α-oxo-benzo[b]thiophen-2-acetamide(See Scheme I, Wherein Q is I₄, Wherein b is zero; y is 2,R₅ ishydrogen, and R₆ is 4-[2-(3,4-dihydroxyphenyl)ethyl])

To a stirred solution of benzo[b]thiophene-2-acetic acid,3-hydroxy-α-oxo (28.01 g, 0.126 mole) and4-(3,4-trimethylsilyloxyphenethyl)aniline (47.1 g, 0.126 mole) aspreparedin Preparation 20 above in dry tetrahydrofuran (400 ml) undernitrogen at -8° to -5° C. is added a solution ofdicyclohexylcarbodiimide (26.9 g, 0.12 mole) in tetrahydrofuran (200 ml)over a period of 35 minutes. After the addition is complete the mixtureisallowed to attain room temperature overnight with stirring.Dicyclohexylurea (23.94 g) is removed by filtration and the filtrate isevaporated to dryness on a rotary evaporator below 55° C. The residue isdissolved in methylene chloride (700 ml) and the solution is kept forthree days in a cooler. After removal of dicyclohexylurea (1.2 g)byfiltration, the filtrate is chromatographed on silica gel (490 g).Elution of the column with methylene chloride, gives 60.8 g of aresidue, which is refluxed in methanol (3.5 l), and 2N aqueoushydrochloric acid (75 ml) for 80 minutes with stirring. The solution iscooled. The solid isfiltered off and washed with methanol to give 36.2 g(66.3%) of a light-yellow crystalline solid, mp 197199° C.

Additional 5.9 g (10.8%) of pure product, mp 196°-8° C. is obtained fromthe mother liquid.

The same compound as is prepared in Example 133 above is prepared in analternate process as exemplified in the following example.

EXAMPLE 134N-[4-[2-(3,4-Dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-α-oxo-benzo[b]thiophene-2-acetamide

Benzo[b]thiophene-2-acetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-60-oxo (29.8 g,0.064mole) in methylene chloride (1.4 l), is added dropwise at -70° C.boron trimbromide (0.325 mole, 325 ml of 1M solution in methylenechloride), over a period of one hour. The mixture is stirred at roomtemperature overnight. The mixture is cooled in acetone-dry ice andwater (˜750 ml) is added. The mixture is stirred at room temperature fortwo hours. The precipitate is filtered off and washed with water (˜2.5l). The resulting solid is dissolved in methanol (2.5 l), water (1 l),and refluxed on a steam bath for 2.5 hours. The methanol (˜1.2 l) isdistilled off and water (˜1 ) is added. After refluxing for one hour,the warm mixture is filtered. The residue is washed with water anddried. The solid is recrystallized from methanol to give 17.45 g (62.3%)of a light-yellow crystalline solid, mp 193°-5° C.

In a manner again analogous to Example 131 or 132 the followingcompounds are prepared using appropriate starting material.

EXAMPLE 135 Benzo[b]thiophene-2-acetamide,5-chloro-N-(4-decylphenyl)-3-hydroxy-α-oxo, mp 145°-146° C. EXAMPLE 136Benzo[b]thiophene-2-acetamide,N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl]-3-hydroxy-α-oxo, mp 220°-221°C. EXAMPLE 137 Beno[b]thiophene-2-acetamide,N-[4-[2-(4-chlorophenyl)ethyl]phenyl]-3-hydroxy-α-oxo, mp 210°-212° C.

In a manner analogous to Example 134 using the appropriate startingmaterials for example, prepared in Example 132, the following compoundis prepared.

EXAMPLE 138 Benzo[b]thiophene-2-acetamide,5-chloro-N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-α-oxo,mp248° C. dec

In a manner analogous to Example 132 using the appropriate startingmaterials, the following compound is prepared.

EXAMPLE 139 Benzo[b]thiophene-2-acetamide,5-chloro-N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-α-oxo,mp207°-209° C. EXAMPLE 140 Benzo[b]thiophene-2-acetamide,3-(acetyloxy)-N-[4-(2-(3,4-bis(acetyloxy)phenyl]ethyl)phenyl]-α-oxo-

To a stirred suspension of benzo[b]thiophene-2-acetamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl)phenyl]-3-hydroxy-α-oxo (14.9 g,0.034 mole) in acetic anhydride (100 ml) under nitrogen below 25° C. isadded dropwise pyridine (100 ml), then the mixture is stirred at roomtemperature for 21 hours. The suspension is poured on ice-water (˜1.7 l)stirred for 30 minutes, and the precipitate is filtered off, washed withwater, then dissolved in chloroform (˜800 ml), washed with water (˜1 ),dried with sodium sulfate, and the solvent is removed under reducedpressure on a rotary evaporator below 45° C., to give a solid inquantitative yield, mp 169°-170° C. Recrystallization from methylenechloride-methanol on cooling gives 17.16 g (87.4%) of a light-yellowcrystalline solid, mp 170°-2° C.

EXAMPLE 141 Benzo[b]thiophene-2-acetamide,N-[4-[2-(3,4-bis)acetyloxy)phenyl)ethyl]phenyl]-3-hydroxy-α-oxo

Prepared from 1,2-benzenediol, 4-[2-(aminophenyl)ethyl]diacetate (6.27g, 0.02 mole), benzo[b]thiophene-2-acetic acid, 3-hydroxyα-oxo (4.44g,0.02 mole) and dicyclohexylcarbodiimide (4.13 g, 0.02 mole) inmethylene chloride (500 ml) by the method of Example 112.Dicyclohexylurea is removed by filtration and the filtrate ischromatographed on 630 g of silica gel. Elution of the column with ethylacetate gives 2.6 g of a solid. Recrystallization from methylenechloride-methanol gives 2.28 g (22%) of a light-yellow crystallinesolid, mp 190°-2° C.

EXAMPLE 142 Benzo[b]thiophene-2-acetamide,3-hydroxy-N-[4-[2-(4-hydroxy-3-methoxyphenyl)ethyl]phenyl]-α-oxo-, mp189°-193° C. EXAMPLE 143 Benzo[b]thiophene-2-carboxamide,N-[4-[2-(3,4-dimethoxphenyl)ethyl]phenyl]-3-hydroxy, mp 197°-198° C.EXAMPLE 144 Benzo[b]thiophene-2-carboxamide,N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl-3-hydroxy, mp 193°-5° C.EXAMPLE 145 Benzo[b]thiophene-2-carboxamide,N-[4-[2-(4-chlorophenyl)ethyl]phenyl]-3-hydroxy, mp 216°-220° C. EXAMPLE146 Benzo[b]thiophene-2-carboxamide,N-[3-[2-(3,4-dichlorophenyl)ethyl]phenyl]-3-hydroxy, mp 193°-195° C.EXAMPLE 147 Benzo[b]thiophene-2-carboxamide,N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl]-3-methoxy, mp 162°-163° C.EXAMPLE 148 Benzo[b]thiophene-2-carboxamide,N-[4-[2-[3,5-bis(trifluoromethyl)phenyl]ethyl]phenyl]-3-hydroxy, mp203°-205° C.

VIII. Preparation of Compounds of Formula I Wherein Q is I₅

The starting material for preparing a compound of Formula I, wherein Qis I₅ may be prepared as examplified in the following example.

EXAMPLE 149 4H-Furo[3,2-c][1]benzopyran-2,3-dione (see Scheme VII,Formula XII₅ Wherein R₁ is hydrogen)

To a stirred solution of 4-[(trimethylsilyl)oxy]-2H-1-benzopyran (L. H.Hellberg, and A. Zuarez, Tetrahedron Letters, 40, 3553 (1974)) (205.8 g,0.917 mole) in anhydrous ether (600 ml) oxalyl chloride (58.2 g, 0.458mole) is added dropwise over a period of 40 minutes at room temperatureunder nitrogen. The suspension is stirred at room temperature for 18hoursand then diluted with isopropyl ether (˜300 ml). The precipitate iscollected by filtration and washed with isopropyl ether to give 80.2 g(86%) of orange-red solid, mp 146°-8° C. Recrystallization fromtetrahydrofuranisopropyl ether gives an analytical sample, mp 146°-148°C.

Preparation of compounds of Formula I wherein Q is I₅ are exemplified bythe following examples.

EXAMPLE 150N-[4-[2-(3,4-Dihydroxyphenyl)ethyl]phenyl]-4-hydroxy-60-oxo-2H-1-benzopyran-3-acetamide(See Scheme I, Formula I wherein Q is I₅ wherein R₁ is hydrogen; y is 2,R₅ is hydrogen and R₆ is 4-[2-(3,4-dihydroxyphenyl)ethyl]

Prepared by the method of Scheme I, from from4H-furo[3,2-c][1]benzopyran-2,3-dione as prepared in Example 149 above(5.6 g, 0.0275 mole) and 4-(3,4-dihydroxyphenethyl)aniline (5.73 g,0.025 mole) in tetrahydrofuran (300 ml). The solvent is removed underreduced pressure on a rotary evaporatory below 30° C. and the resultingsolid is chloroform (400 ml) is stirred mechanically at reflux for 40minutes. The precipitate is removed by filtration and washed withchloroform to give 10.2 g of a solid, which is dissolved intetrahydrofuran and chromatographed on silica gel (200 g). Elution ofthe column with tetrahydrofuran gives 9.4 g of a solid.Recrystallization fromethanol yields 6.8 g (63%) of a yellow crystallinesolid, mp 161°-3° C.

EXAMPLE 151N-(4-Decylphenyl)-4-hydroxy-α-oxo-2H-1-benzopyran-3-acetamide (SeeScheme I, Formula I, Wherein Q is I₅, Wherein R₁ is hydrogen; y is 2; R₅is hydrogen; and R₆ is 4-[2-decylphenyl)ethyl]

A mixture of 4H-furo[3,2-c][1]benzopyran-2,3-dione as prepared in 149above(5.6 g, 0.0275 mole) and 4-decylaniline (5.85 g, 0.025 mole) in drytetrahydrofuran (250 ml) is stirrred at room temperature under nitrogenfor 18 hours in the dark. The solvent is removed under reduced pressureona rotary evaporator below 40° C. and the resulting solid isrecrystallized twice from methylene chloride-acetonitrile to give 9.54 g(87.5%) of a light-yellow crystalline solid, mp 119°-120° C.

In a manner analogous to Examples 149 or 150 above, using approriatestarting materials the following compounds of Formula I wherein Q is I₅were prepared.

EXAMPLE 152 2H-1-[Benzopyran-3-acetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-4-hydroxy-α-oxo, mp 170°-171°C. EXAMPLE 153 2H-1-Benzopyran-3-acetamide,N-[4-[2-(4-chlorophenyl)ethyl]phenyl]-4-hydroxy-α-oxo, mp 146°-148° C.EXAMPLE 154 2H-1-Benzopyran-3-acetamide,N-[4-[2-(4-hydroxy-3-methoxyphenyl)ethyl]phenyl-4-hydroxy-α-oxo EXAMPLE155 2H-1-Benzopyran-3-acetamide,N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl]-4-hydroxy-α-oxo, mp 159°-160°C.

IX. Preparation of Compounds of Formula I Wherein Q is I₆

The preparation for a compound of Formula I wherein Q is I₆ isexemplified in the immediately following examples.

EXAMPLE 156 2H-Furo[3,2-b]indole-2-acetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3,4-dihydro-7-methoxy-α,3-dioxo-4-phenyl(See Scheme I, Formula I Wherein Q is I₆ Wherein R₁ is 7-methoxy; b isone; R₂ is hydrogen; R₅ is hydrogen; y is 2; R₆ is4-[2-(3,4-dimethoxyphenyl)ethyl])

A mixture of 2.4 g (0.050 mole) of 50% sodium hydride mineral oilsuspension is 150 ml of N,N-dimethylformamide under a nitrogenatmosphere was stirred and cooled in ice. To the mixture was added over30 minutes, 13.4 g (0.048 mole) of7-methoxy-4-phenyl-2H-furo[3,2-b]indole-3(4H)-one. After stirring for anadditional one hour, 18.9 g (0.053 mole) of[4-[2-(3,4-dimethoxyphenyl)ethyl]phenylamino]oxoacetic acid ehtyl esterwas added, and the ice bath was removed.

The mixture was stirred for 48 hours, added to 1.0 kg ice/water, andacidified with 3N hydrochloric acid. The precipitated solid wasfiltered, washed with water, and recrystallized fromN,N-diethylformamide/water to yield 18.6 g (66% yield) of amide product,mp 261°-263° C.

EXAMPLE 157 2H-Furo[3,2-b]indole-2-carboxamide,N-[4-[2-(4-methoxyphenyl)ethyl]phenyl]-3,4-dihydro-4-methyl-3-oxo (seeScheme I, Formula I Wherein Q is I₆ Wherein b is zero, R₂ is methyl; yis 1; R₅ is hydrogen; and R₆ is 4[2-(4-methoxyphenyl)ethyl])

Prepared by the procedure described in Example 156 above from 5.0 g(0.027 mole) of 4-methyl-2Hfuro[3,2-b]indole-3(4H)-one, except that[4-[2(4-methoxyphenyl)ethyl]phenyl-N,N-diphenyl urea (12.4 g, 0.029mole) was employed as the acylating agent rather than the mixedester-amide usedin the Example 156. Recrystallization of the finalproduct from 2-mehoxyethanol yielded 5.0 g (43% yield) of the amideproduct, mp 224°-226° C.

EXAMPLE 158 2H-Furo[3,2-b]indole-2-carboxamide,N-[4-[2-(3,4-Dimethoxyphenyl)ethyl]phenyl-3,4P-dihydro-7-methoxy-3-oxo-4-phenyl(See Scheme I, Formula I Wherein Q is I₆ Wherein R₁ is 7-methoxy, R₂ isphenyl, R₅ is hydrogen; and R₆ is 4-[2-(3,4-dimethoxyphenyl)ethyl])

A mixture of 16.6 g (23.0 ml, 0.16 mole) of diisopropylamine in 150 mlof tetrahydrofuran under a nitrogen atmosphere was cooled to 0° to -10°C. in an ice/sodium chloride cooling bath. The mixture was stirred andtreated over 20 minutes with a solution of 63 ml (0.16 mole) of n-butyllithium (2.6M in n-hexane) at a rate that allowed the reaction mixturetemperature to remain at <0° C. The mixture was stirred foran additional20 minutes, and then a solution of 20.0 g (0.078 mole) of4-[2-(3,4-dimethoxyphenyl)ethyl]benzenamine in 150 ml of tetrahydrofuranwas added over 30 minutes. After stirring for an additional 40 minutes,a solution of 18.0 g (0.053 mole) of3-hydroxy-7-methoxy-4-phenyl-4H-furo[3,2-b]indole-2-carboxylic acidmethylester (Preparation described in U.S. patent application Ser. No.369,448 now issued as U.S. Pat. No. 4,503,236) in 150 ml of1,3-dimethyl-2-imidazolidinone was added over 45 minutes. The mixturewas stirred with the cooling bath in place for an additional 45 minutes,then for 18 hours with the bath removed. The reaction mixture was addedto 2.5 kg of ice/water containing 50 ml of concentrated hydrochloricacid. After stirring for two hours, the precipitated product wasfiltered, washed withwater, and recrystallized from2-methoxyethanol/water to yield 10.6 g (35% yield) of the amide product,mp 180° C. dec.

The next two examples show ether cleavage to prepare compounds ofFormula Iwherein R₆ included hydroxy substituents.

EXAMPLE 159 4H-Furo[3,2-b]indole-2-carboxamide,N-[4-[2-(3,4-Dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-4-methyl (SeeFormulaI Wherein Q is I₆, Wherein b is zero, R₂ is mehtyl; R₅ ishydrogen; y is 1; R₆ is 4-[2-(3,4-dihydroxyphenyl)ethyl])

A mixture of 10.6 g (0.034 mole) of boron tribromide dimethyl sulfidecomplex in 125 ml of 1,2-dichloroethane was treated, under a nitrogenatmosphere, with 1.9 g (0.004 mole) ofN-[4-[2-(3,4-dimethoxyphenyl)ehtyl]phenyl]-3-hydroxy-4-methyl-4H-furo[3,2-b]indole-2-carboxamide.The mixture was stirred at reflux for 18 hours, cooled in ice, andtreated with 150 g ice/water. After mixture was stirredat reflux for 18hours, cooled in ice, and treated with 150 g ice/water. After stirringfor several hours, the insoluble material was filtered and washed withwater. Recrystallization from acetonitrile/N,N-dimethylformamide/wateryielded 1.1 g (59% yield) of the catechol product, mp 200° C. dec.

EXAMPLE 160 2H-Furo[3,2-b]indole-2-carboxamide,N-[4-[2-(4-hydroxyphenyl)ethyl]phenyl-3,4-dihydro-4-methyl-3-oxo (SeeFormula I Wherein Q is I₆, Wherein b is zero, R₂ is methyl, y is1, R₅ ishydrogen; R₆ is 4-[2-(4-hydroxyphenyl)ethyl])

A mixture of 4.0 g (0.009 mole) of3,4dihydro-N-[4-[2-(4-methoxyphenyl)ethyl]phenyl]-4-methyl-3-oxo-2H-furo[3,2-b]indole-2-carboxamidein 125 ml of dichloromethane under a nitrogen atmosphere was cooled to-78° C. To the mixture was added 39 ml (0.039 mole) of 1.0M solution ofboron tribromide in dichloromethane. The cooling bath was removed, andthe mixture was stirred for 18 hours. The mixture was recooled in an icebath and treated with 500 g ice/water and 500 ml ethyl acetate. Theinsoluble material was filtered and reserved, and the filtrate organiclayer was separated, dried (sodium sulfate), and evaporated. Theevaporation residue was combined with the original insoluble materialand recrystallized from acetonitrile to yield 1.8 g (47% yield) of thephenol product, mp 261°-262° C.

In an analogous manner as the above Examples 151-160 for the respectiveprocedures using appropriate starting materials the following additionalcompounds are prepared.

EXAMPLE 161 4H-Furo[3,2-b]indole-2-carboxamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-4-methyl, mp200°-201° C. EXAMPLE 162 2H-Furo[3,2-b]indole-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ehyl]phenyl]-3,4-dihydro-7-hydroxy-4-phenyl-.alpha.,3-dioxo,1 DMF, mp 265° C. dec EXAMPLE 163 2H-Furo[3,2-b]indole-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3,4-dihydro-7-hydroxy-3-oxo-4-phenyl,225° C. dec EXAMPLE 164 2H-Furo[3,2-b]indole-2-acetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3,4-dihydro-4-methyl-α,3-dioxo,0.4H₂ O, mp 250°-254° C. EXAMPLE 165 2H-Furo[3,2-b]indole-2-acetamide,N-[4-[2-(3,4-dihdroxyphenyl)ethyl]phenyl]-3,4-dihydro-4-methyl-α,3-dioxo,0.5 DMF, mp 257°-8° C. EXAMPLE 166 2H-Furo[3,2-b]indole-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3,4-dihydro-3-oxo-4-phenyl,0.5H₂ O, 192° C. dec

X. Preparation of Compounds of Formula I Wherein Q is I₇

Intermediate ethers and compounds of Formula I of the present inventionwherein Q is I₇ prepared by the method of cleaving the ethers are shownin Scheme IX and exemplified hereafter.

EXAMPLE 167 1H-Indole-2-carboxamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-methoxy-1-phenyl (SeeScheme IX, Formula XI₇ Wherein b is zero, R₂ is methyl, R₃ is methyl; yis one, X is hydrogen; R₅ is hydrogen; R₆ is4-[2-(3,4-dimethoxyphenyl)ethyl])

A mixture of 8.0 g (0.030 mole) of3-methoxy-1-phenyl-1H-indole-2-carboxylic acid and 7.8 g (0.030 mole) of4-[2-(3,4-dimethoxyphenyl)ethyl]benzenamine in 125 ml of dichloromethanewas cooled in ice and treated with 8.6 ml (6.2 g, 0.030 mole) oftriethylamine, followed by 7.7 g (0.030 mole) ofN,N-bis[2-oxo-3-oxazolidinyl]phosphorodiamidic chloride (ChemicalDynamicsCorp., South Plainfield, NJ). The ice bath was removed, and themixture wasstirred for 48 hours, then treated with 250 g of ice/water.The mixture wasacidified with 4.0N hydrochloric acid, and the organiclayer was separated.The aqueous layer was washed with freshdichloromethane (2×100 ml) and the combined organic layers were washedwith water (1×125 ml), 5% aqueous sodium bicarbonate (2×125 ml), andwater (1×125 ml)again. The organic layer was dried (sodium sulfate) andevaporated. Recrystallization of the residue frommethanol/N,N-dimethylformamide/wateryielded 9.7 g (64% yield) of theamide product, mp 129°-131° C.

EXAMPLE 168 1H-Indole-2-carboxamide,N-[4-[2-(3,4-Dimethoxyphenyl)ethyl]phenyl]-3-methoxy-1-methyl (SeeScheme IX, Formula XI₇ Wherein b is zero, R₂ is methyl, R₃ is methyl; Xis hydrogen, and R₆ is 4-[2-(3,4-dimethoxyphenyl)ethyl])

A mixture of 10.7 g (0.052 mole) of3-methoxy-1-methyl-1H-indole-2-carboxylic acid and 14.0 g (0.056 mole)of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline ("EEDQ") in 185 ml oftoluene was stirred at room temperature for two hours. To the mixturewas added 14.1 g (0.055 mole) of4-[2-(3,4-dimethoxyphenyl)ethyl]benzenamine, and stirring was continuedfor 72 hours. The mixture was refrigerated for several hours, and theinsoluble material was filtered and washed with water. Recrystallizationfrom methanol yielded 9.7 g (42% yield) of the amide product, mp130°-131° C.

EXAMPLE 169 1H-Indole-2-carboxamide,N-[4-[2-(3,4-Dimethoxyphenyl)ethyl]phenyl]-N-ethyl-3-methoxy-1-methyl(SeeScheme IX, Formula XI₇ Wherein b is zero, R₂ is methyl, R₃ ismethyl, X is ethyl; R₅ is hydrogen; y is 1; R₆ is4-[2-(3,4-dimethoxyphenyl)-ethyl])

A mixture of 2.7 g (0.048 mole) of powdered potassium hydroxide in 23 mlofdimethyl sulfoxide was stirred for five minutes and treated with 5.3 g(0.012 mole) ofN-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-methoxy-1-methyl-1H-indole-2-carboxamide,followed by 2.0 ml (3.8 g, 0.024 mole) of iodoethane. The mixture wasstirred at room temperature for 20 hours, poured into 300 ml water, andextracted with dichloromethane (3×300 ml). The combined organic layerswere washed with water (1×200 ml), dried (sodium sulfate), andevaporated. Recrystallization of the residue from methanol yielded 4.3 g(76% yield) of the N-ethylamide product, mp 133°-134° C.

In a manner analogous to Examples 167-169 using appropriate startingmaterials the following additional intermediates are prepared.

EXAMPLE 170 1H-Indole-2-carboxamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-N-ethyl-3,5-dimethoxy-1-phenyl(oil) EXAMPLE 171 1H-Indole-2-carboxamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-methoxy, mp 187°-190° C.EXAMPLE 172 1H-Indole-2-carboxamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-5-methoxy-1-phenyl-3-(phenylmethoxy),mp 120.5°-122.5° C. EXAMPLE 173 1H-Indole-2-carboxamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3,5-dimethoxy-1-phenyl, mp147°-149° C. EXAMPLE 174 1H-Indole-2-carboxamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-methoxy-1-(phenylmethyl),mp 131°-133° C. EXAMPLE 175 1H-Indole-2-acetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-5,6-dimethyl-α-oxo(See Scheme IX, Formula I Wherein Q is I₇ Wherein b is two, R₁ is5,6-dimethyl; R₂ is hydrogen; X is hydrogen; y is 2; R₅ is hydrogen, R₆is 4-[2-(3,4-dimethoxyphenyl)ethyl])

A mixture of 12.5 g (0.054 mole) of3-hydroxy-5,6-dimethyl-α-oxo-1H-indole-2-acetic acid (Preparationdescribed in U.S. Pat. No. 4,260,544) and 14.4 g (0.058 mole) ofN-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline ("EEDQ") in 1500 ml oftoluene plus 200 ml of tetrahydrofuran was stirred at room temperatureforthree hours. To the mixture was added 14.5 g (0.056 mole) of4-[2-(3,4-dimethoxyphenyl)ethyl]benzenamine, and stirring was continuedfor 64 hours. The insoluble material was filtered and reserved, and thefiltrate was evaporated. The residue was combined with the originalinsoluble material and recrystallized from dichloromethane/hexane toyield4.0 g (16% yield) of the amide product, mp 233°-236° C.

Ether clearage for dimethyl ethers of compounds having the Formula Iwherein Q is I₇ is exemplified as follows.

EXAMPLE 176 1H-Indole-2-carboxamide,N-[4-[2-(3,4-Dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-1-methyl (SeeScheme IX, Formula I Wherein Q is I₇, Wherein b is zero; y is 1; R₂ ismethyl; X is hydrogen; R₅ is hydrogen; R₃ is hydrogen; R₆ is4-[2-(3,4-dihydroxyphenyl)ethyl])

A mixture of 3.3 g (0.0074 mole) ofN-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-methoxy-1-methyl-1H-indole-2-carboxamidein 115 ml of dichloromethane under a nitrogen atmosphere was stirred andcooled to -78° C. To the mixture was added 31.3 ml (0.031 mole) of 1.0Mboron tribromide in dichloromethane. The mixture was stirred for 90minutes at -78° C., and then for 24 hours with the cooling bath removed.The mixture was recooled in an ice bath, treated with 300 g ice/waterand 300 ml of ethyl acetate. After stirring for several hours, thelayers were separated and the aqueous layer was extracted with freshethyl acetate (2×300 ml). The combined organic layers were washed withwater (1×300 ml), dried (sodium sulfate), and evaporated.Recrystallization of the residue from methanol/water yielded 1.8 g, 60%yield) of the catechol product, mp 194°-197° C. dec.

EXAMPLE 177 1H-Indole-2-acetamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-5,6-dimethyl-α-oxo(See Scheme IX) Formula I Wherein Q is I₇ Wherein R₁ is 5,6-dimethyl; bis two; y is two; R₅ is hydrogen; R₃ is hydrogen; R₆ is4-[2-(3,4-dihydroxyphenyl)ethyl])

A mixture of 9.7 g (0.031 mole) of boron tribromide dimethylsulfidecomplexin 150 ml of 1,2-dichloroethane under a nitrogen atmosphere wastreated with 3.0 g (0.0064 mole) ofN-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-5,6-dimethyl-α-oxo-1H-indole-2-acetamide.The mixture was stirred at reflux for 18 hours, cooled, and treated with600 g of ice/water. After stirring for several hours, the insolublematerial was filtered, washed with water, and refiltered.Recrystallization from acetonitrile/N,N-dimethylformamide/water yielded0.31 g (11% yield) of catechol product, mp 239°-241° C.

In a manner analgous to the respective Examples 175-176 usingappropriate starting materials the following compounds of Formula I,Wherein Q is I₇ are prepared.

EXAMPLE 178 1H-Indole-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-, mp 236°-238° C.EXAMPLE 179 1H-Indole-2-acetamide,N-(4-decylphenyl)-3-hydroxy-5,6-dimethyl-α-oxo, mp 210°-211° C.

The usefulness of the compounds of the present invention as inhibitorsof lipoxygenase enzyme or antagonists of leukotriene or other relatedbiochemical actions is demonstrated by their effectiveness in variousstandard pharmacological test procedures. A description of eachprocedure follows.

Human Leukocyte Lipoxygenase Assay (LDA-H)

Whole blood is collected from normal volunteers and spun in arefrigerated centrifuge for four minutes at 1°-6° C. at 3800 g. Thebuffycoat is manually separated and washed twice with chilled 0.83% NH₄Cl and centrifuged at 1000 RPM for ten minutes at 4° C. The white cellissuspended in culture media-EMEM supplemented with 6% Agamma humanserum,tricine buffer, and neomycin and recentrifuged at 1000 g to yielda pellet containing the leukocytes used for the preparation of theacetone pentane powder.

The acetone-pentane powder is prepared utilizing a modification of theprocedure reported for human platelet lipoxygenase. See Siegel, et al,Arachidonate Metabolism via Lipoxygenase and 12-L-hydroperoxy-5Eicosatetraenoic Acid Peroxidase Sensitive to Antiinflammatory Drugs,Proc. Natl. Acad. Sci., USA 77: 308, 1980 and D. P. Wallach and V. R.Brown, A Novel Preparation of Human Platlet Lipoxygenase, Biochem.Biophys. Acta. 663: 361, 1981. Buffy coat prepared above is resuspendedin5-7 volumes of cold 0.1M Tris buffer, pH 7.4 containing 0.154M NaCl.The suspension is centrifuged at 13,300 g for ten minutes at 4° C. Theresultant pellet is retained, resuspended in five volumes of coldacetone,recentrifuged at 13,300 g and resuspended in five volumes ofcold pentane. The pentane suspension is centrifuged for ten minutes at13,300 g to give a pellet which is dried in the cold under vacuum withperiodic pulverization. The dry powder is stable for several weeks whenstored at -80° C.

Enzyme stock solution is prepared in the following manner. About 15 mgof the acetone-pentane powder is suspended in 4 ml of cold tris buffer(0.1M,pH 7.4), allowed to stand for five minutes, and homogenizedthoroughly. Thehomogenate is sonicated three times for 15 seconds eachtime, diluted to 7 ml with cold tris buffer (0.1M, pH 7.4), andcentrifuged at 4° C. for 60 minutes at 13,300 g. the supernatent isretained and diluted to a total of 10 ml with cold tris buffer (0.1M, pH7.4) to give the stock enzyme solution. Additional dilutions of 2-50fold are done as necessary to locate optimal enzyme reaction rate in theassay described below.

Substrate solution is prepared at 100 μM or 1.0 μM concentrations ofarachidonic acid or linoleic acid in 0.1M tris buffer, pH 9.0 containing20% ethanol.

The enzyme reaction is followed spectrophotometrically by the appearanceofa conjugated diene product at 234 nm. The reaction is monitored at 24°C. using a Gilford Model 2600 spectrophotometer. Each assay hada totalvolume of 1.0 ml and contained substrate, tris buffer (0.1M, pH 9.0), 2%ethanol, and sufficient enzyme to give an easily measurable initial rateof reaction. The effects of inhibitors on the reaction are compared withcontrol reactions run under indentical conditions. Routinely, eachcompounds of the present invention is incubated with the enzyme for fiveminutes prior to addition of substrate to initiate the reaction.Inhibition expressed as IC₅₀ as molar concentration of the compoundrequired to reduce reaction rate to 50% control.

Binding of ³ H-Leukotriene D₄ to Guinea Pig Lung Membranes (RBL)

Materials

[14,15-³ H]leukotriene D₄ (³ H-LTD₄) (25 Ci/mmol and 40Ci/mmol) ispurchased from New England Nuclear. Unlabeled LTC₄ is a gift of OnoPharmaceuticals (Japan). LTC₄, LTD₄, and LTE₄ are purchased as methylesters from Paesel GmbH (Frankfurt, W. Germany). Concentrations of thePaesel leukotrienes are calculated from their absorbance at 280 nm.Leukotriene esters are saponified overnight under N₂ in 3.3% potassiumcarbonate at room temperature. Tritiated leukotrienes are stored asreceived from New England Nuclear at -20° C. Ono LTC₄ (5 μg/ml) isstored at -60° C. in phosphate buffer pH 6.8. Saponified Paeselleukotrienes are stored at -60° C. in 3.3% potassium carbonate (pH9.0-9.5). Aliquots of leukotrienes are taken from stock solutionsimmediately after thawing, after which the stock solutions areimmediately refrozen. 2-Amino-2-(hydroxymethyl)-1,3-propanediol (Tris)is Sigma pH 7.7 pre-set crystals, and dimethylsulfoxide is Aldrich GoldLabel.

Preparation of crude lung membranes

Two pairs of lungs (1.3 g) from freshly sacrificed 300 g male guineapigs (older animals gave substantially lower binding) from Kuiper RabbitFarm, Gary, IN are disrupted with a Polytron PT 10 (setting 4) for 30seconds in20 ml ice-cold 50 mM Tris adjusted with HCl to pH 7.7 at 25°C. (Tris buffer), filtered through a single layer of gauze to removeconnective tissue, and centrifuged at 50,000 xg for ten min. The pelletisresuspended by homogenization with a Polytron in 20 ml Tris buffer,centrifuged at 50,000 xg for ten min., resuspended, incubated at 37° C.for 30 minutes, and centrifuged again. The final pellet is resuspendedin Tris buffer and either used fresh or stored at -70° C.

Binding assay

All incubations are in triplicate for 60 minutes at 25° C. in 12×75 mmpolystyrene tubes containing 1 ml Tris buffer with 20 mg original tissuewet weight of guinea pig lung nmembranes, 0.2 nM ³ H-LTD₄ (6,000-11,000cpm), 10 mM MgCl₂, and 1% dimethylsulfoxideLeukotrienes are diluted inTris buffer. All other test compounds dissolvedat 10 mM indimethylsulfoxide on the same day as the experiment, and diluted indimethylsulfoxide to 100× the final incubation concentration. Controlincubations receive an equal volume (10 μl) of dimethylsulfoxide; theresulting concentration of dimethylsulfoxide had noeffect on binding. ³H-LTD₄ is diluted to 2 nM in Tris buffer. The membrane suspension (20mg/0.89 ml) contains sufficient MgCl₂ to give 10 mM final concentrationin the incubation. For test compounds with IC₅₀ values less than 1 μM,the order of incubations is test compound (10 μ l), ³ H-LTD₄ (100 μl),and membranes (0.89 ml). For test compounds with IC₅₀ values greaterthan 1 than 1 μM and limited water solubility, the order of additions istest compound, membranes, and ³ H-LTD₄. All additions are performed at0° C. Immediately after the last addition, the incubation is initiatedby agitating the rack of tubes on a vortex mixer and warming to 25° C.in a water bath. Tubes are vortexed at least once more during theincubation to ensure that the membranes remained suspended. Incubationsare terminated after 60 minutes by filtering under reduced pressurethrough 25 mm Whatman GF/B filters followed by rapid washing three timeswith 4 ml of ice-cold Tris buffer. Filters are added to scintillationvials with 8 ml Formula 947 (New England Nuclear), left overnight,shaken, and the radioactivity counted in a scintillation counter(efficiency 40%). Nonspecific binding, defined as binding of ³ H-LTD₄ inthe presence of 100 nM LTC₄, is 300-500 cpm forall lots of ³ H-LTD₄.Binding to the filters in the absence of tissue is about 100 cpm, and isnot affected by unlabeled LTC₄. Specific binding, defined as totalbinding minus nonspecific binding, varied considerably from lot to lotof ³ H-LTD₄. Specific ³H-LTD₄ binding ranged from 1500 to 3000 cpm, andis greater than 80% of total binding for the better lots of ³ H-LTD₄.

To Evaluate the Effect of Each Compounds as a 5-Lipoxygenase Inhibitorin Comparison to Standard Reference Agents in Human Leukocytes (5LOA1)

The purpose of this assay is to evaluate the activity of each compoundas an inhibitor of human leukocyte 5-lipoxygenase.

Arachidonic acid and calcium ionophore A23187 are obtained from Sigma(St. Louis, MO). Silica gel plates, GF are obtained from Analtech(Newark, DE).Arachidonic acid, (1-¹⁴ C) and 5-HETE (³ H), 5(S)-hydroxy-6-trans,8,11,14-cis eicosatetraenoic acid, are obtained fromNew England Nuclear (Boston, MA). Six percent Dextran-70 in 0.9% NaCl isobtained from Cutter Labs (Berkeley, CA).

Preparation of Leukocytes

Fresh blood from normal adult men who had not received any drugs for atleast the previous five days is obtained by the Community ResearchClinic (WL/PD) using venipuncture and collected into heparinizedvacuotainer tubes. To every 100 ml of pooled blood is added 25 ml ofdextran solution (6% dextran -70 in 0.9% sodium chloride containing 3%dextrose) and this is mixed gently in a plastic cylinder. The mixture isleft to stand at room temperature for at least 90 minutes. The upperlayer which is rich inleukocytes and platelets is then carefullydecanted into 50 ml plastic tubes and centrifuged at about 100×g foreight minutes in an IEC centrifuge and rotor number 269 (about 600 rpm).The supernatant fluid is discarded and the pellet is resuspended in 10ml of 0.87% ammonium chloride for exactly two minutes. This procedure isto lyse completely contaminating red blood cells. Leukocytes are thenseparated by centrifugation for ten minutes. The pellet is washed threetimes by suspension in 20 ml PBS (sodium chloride, 7.1 g; Na₂ HPO₄, 1.15g; KH₂ PO₄, 0.2 g, and KCl, 0.2 g/L) and centrifuged as before. Thefinal pellet is suspended in PBS containing 0.87 mM CaCl₂. Viability ofthe cells is then checked using trypan blue exclusion method and isfound to be over 90%.

5-Lipoxygenase Enzyme Assay

Leukocyte cells in suspension (0.98 ml) are incubated with or withouttest compounds for five minutes at 37° C. in a shaking water bath. Atthis time a 17 μl mixture is prepared per 1 ml of cell suspension: 100mM arachidonic acid, 1 μl, 0.05 μCi ¹⁴ C-arachidonic acid in 5 μl; 1 mMcalcium ionophore A23187, 10 μl (1). This mixture is added and theincubation continued for five minutes. The reaction is stopped by addingfour volumes of absolute ethanol and the mixture is kept in ice for30minutes. The floculated precipitate is separated by centrifugation atabout 37,000×g for 20 minutes (Beckman Instruments rotor number 40).Thealcohol extract is taken to dryness under a stream of nitrogen and theresidue is dissolved in 100-200 μl absolute ethanol. At the time anyturbidity is removed by centrifugation. An aliquot (25-50 μl) is appliedonto 20×20 cm silica gel TLC plate and developed using the followingsolvent system: diethyl ether, petroleum ether (2040° C.), acetic acid(50:50:1 v/v). Zones of 1 cm apart are scraped from the TLC plate andtransferred to mini-vials. Methanol (0.5 ml) is added to dissolve theradioactivity adsorbed to the silica gel and scintillation fluid (H. P.,Beckman), 5 ml is then added and vials are counted in a liquidscintillation counter. A sample of ³ H-5-HETE is applied and used forthe identification of the formed 5-HETE.

Total radioactivity in the test as well as the control samples arenormalized and the amount of 5-HETE present is calculated accordingly.

IC₅₀ values are defined as the concentrations of test agents whichcaused a 50% inhibition of the formation of 5-HETE as compared tocontrol and are determined by inspection of the concentration-responsecurves.

5-Lipoxygenase Assay Using Isolated Human Leukocytes (5LOA₂)

The formation of 5-HETE in human leukocytes is considered a measure of5-lipoxygenase activity. The protocol is described in the following.

Fresh heparinized or EDTA treated human blood is mixed with 6%dextran-3% dextrose in isotonic saline in the ratio 0.25 ml dextransolution per 1.0 ml blood. After mixing the blood is allowed to sit atroom temperature forabout 90 minutes while the RBC's settle. During thisperiod, the plasma is removed with a plastic pepette to nalgens tubes.

The plasma is centrifuged at 800 rpm (125 kg) on the Beckman Td-brefrigerated centrifuge to remove the platelets (which remain in thesupernatant). The pellet, consisting of leukocytes and erythrocytes, istreated with 10 ml 0.87% ammonium chloride at room temperature for fourminutes, lysing the red cells. At the end of four minutes the cells arediluted with a 2x volume of phosphate buffered saline, pH 7.4, andcentrifuged for ten minutes. The cells are washed three times with thephosphate buffered saline. Any of the pelleted cell matter which is noteasily resuspended is discarded during the washings--the materialcontainsplatelets (12-lipoxygenase activity)

After washing, the cells are resuspended in phosphate buffered salinecontaining 1.0 mM calcium and 0.5 mM magnesium. After counting the cellsare diluted to 1.5-2.0×10⁷ leukocytes per milliliter.

To each polypropylene reaction tube is added 0.48 ml leukocytes in Ca-Mgphosphate buffered saline, pH 7.4; 1-5 μl test compound dissolved inDMSO and buffer; or DMSO for control tubes.

The tubes preincubate at 37° C. for five minutes.

The reaction is started by adding 20 μl of the following, 0.5 μl 20 mMarachidonic acid--final concentration=20 μm; 1 μl 5 mM calcium ionophoreA23187--final concentration=10 μm; and 18.5 μl buffer.

The reaction proceeds for five minutes, then is stopped by adding 0.5 ml0.5 mM ice cold Tris buffer, pH 8.0. The tubes are chilled on ice forten minutes and then extracted three times with a total of 3.5 ml ethylacetate (3.0 ml removed).

The tubes can be stored at this point. For extended storage, the tubesshould be filled with nitrogen.

The ethyl acetate is evaporated with a Sorvall Speed-Vac. The residue isdissolved in ethanol. The tubes can also be stored at this point at -20°C. under nitrogen.

A portion of the ethanol solution is injected into the HPLC system for5-HETE quantitation.

The HPLC system consists of Hewlett-Packard 1040A UV spectrophotometrysystem with an HP85 computer. Injections are made automatically with aWaters WISP 710B. The pump is a Spectra Physics SP8700. Peaks aremeasuredwith a Hewlett Packard 3390A integrator. An RP C-18 column isused. The solvent system is isocratic; the solvent is 70% methanol and30% 0.01M sodium acetate, pH 5.7, pumped at 1.0 ml/min. The flow ismonitored at 235nm for 5-HETE quantitation. Using a 15 cm AlltechNucleosil C-18 5 μM column provides for a sample turnaround time ofabout 16 minutes.

IC₅₀ is calculated as the amount of test agent that causes 50%inhibition of the formation of 5-HETE relative to the control.

The above defined values for each of tested compounds of the presentinvention having the noted Q groups is as found in the following TABLES.

                  TABLE 1                                                         ______________________________________                                        Q is I.sub.1                                                                          Concentration (M)                                                                             % Inhibition                                          ______________________________________                                        Example 18                                                                    RBL       7.19 E -5         50.0    IC                                        5LOA      1.35 E -5         50.0    IC                                        Example 16                                                                    RBL       1.28 E -5         50.0    IC                                        5LOA      1.77 E -5         50.0    IC                                        LDAH      5.10 E -5         50.0    IC                                        Example 41                                                                    RBL       1.26 E -5         50.0    IC                                        LDAH      4.50 E -5         50.0    IC                                        5LOA      7.00 E -6         50.0    IC                                        Example 40                                                                    RBL       5.60 E -5         50.0    IC                                        LDAH      8.20 E -5         50.0    IC                                        Example 44                                                                    RBL       3.02 E -6         50.0    IC                                        5LOA      4.00 E -5         30.0                                                        2.00 E -5         +5.8                                                        1.00 E -5         +19.6                                             LDAH      2.50 E -5         0.0                                               Example 45                                                                    RBL       9.44 E -6         50.0    IC                                        LDAH      8.00 E -5         0.0                                               Example 54                                                                    RBL       1.09 E -5         50.0    IC                                        5LOA      5.25 E -6         50.0    IC                                        LDAH      3.50 E -6         50.0    IC                                        Example 46                                                                    RBL       2.15 E -5         50.0    IC                                                  1.87 E -5         50.0    IC                                        5LOA      1.10 E -5         50.0    IC                                        LDAH      1.10 E -5         50.0    IC                                        Example 39                                                                    RBL       2.48 E -5         50.0    IC                                        LDAH      5.70 E -5         50.0    IC                                        Example 55                                                                    RBL       1.00 E -4         100.0                                                       1.00 E -6         5.0                                                         2.00 E -6         10.0                                                        5.00 E -6         13.0                                                        1.00 E -5         6.0                                                         2.00 E -5         12.0                                                        5.00 E -5         11.0                                                        1.00 E -4         21.0                                              LDA       6.80 E -5         50.0    IC                                        Example 47                                                                    RBL       1.11 E -5         50.0    IC                                        LDAH      8.00 E -5         0.0                                               Example 82                                                                    RBL       3.95 E -5         50.0    IC                                        LDAH      8.00 E -5         0.0                                               Example 12                                                                    RBL       1.00 E -5         0.0                                                         1.00 E -4         0.0                                               LDAH      3.40 E -6         50.0    IC                                        Example 35                                                                    RBL       4.23 E -5         50.0    IC                                        Example 30                                                                    RBL       2.26 E -5         50.0    IC                                        Example 28                                                                    RBL       5.00 E -5         50.0    IC                                                  3.56 E -5         50.0    IC                                        Example 32                                                                    RBL       2.35 E -5         50.0    IC                                        Example 37                                                                    RBL       1.90 E -5         50.0    IC                                        LDAH      8.00 E -5         0.0                                               Example 38                                                                    RBL       6.68 E -6         50.0    IC                                        LDAH      2.50 E -5         0.0                                               Example 43                                                                    RBL       2.06 E -5         50.0    IC                                        LDAH      8.00 E -5         0.0                                               Example 27                                                                    RBL       1.06 E -4         50.0    IC                                        5LOA      1.80 E -5         50.0    IC                                        RBL       1.20 E -4         50.0    IC                                        Example 51                                                                    RBL       3.84 E -6         50.0    IC                                        5LOA      2.12 E -6         50.0    IC                                        LDAH      2.50 E -5         0.0                                               Example 21                                                                    5LOA      7.00 E -7         50.0    IC                                        LDAH      8.20 E -6         50.0    IC                                        Example 22                                                                    LDAH      1.30 E -5         50.0    IC                                        Example 38                                                                    RBL       2.65 E -5         50.0    IC                                        LDAH      8.00 E -5         0.0                                               Example 29                                                                    RBL       3.92 E -5         50.0    IC                                        Example 23                                                                    LDAH      2.50 E -5         0.0                                               Example 14                                                                    LDAH      2.50 E -5         0.0                                               Example 3                                                                     LDAH      2.50 E -5         0.0                                                         1.00 E -5         0.0                                               Example 34                                                                    RBL1      1.58 E -5         50.0    IC                                        Example 60                                                                    5LOA      5.00 E -6         7.9                                                         1.00 E -5         25.2                                                        2.00 E - 5        21.7                                              LDAH      2.50 E -5         50.0    IC                                        RBL       1.21 E -5         50.0    IC                                        Example 48                                                                    RBL       6.48 E -6         50.0    IC                                                  1.19 E -5         50.0    IC                                                  2.00 E -5         50.0    IC                                                  1.29 E -5         50.0    IC                                        5LOA      1.59 E -5         50.0    IC                                                  1.91 E -5         50.0    IC                                        LDAH      2.50 E -5         0.0     IC                                        Example 31                                                                    RBL       5.20 E -5         50.0    IC                                        Example 36                                                                    RBL       1.00 E -4         78.0                                                        2.00 E -6         6.0                                                         5.00 E -6         3.0                                                         1.00 E -5         7.0                                                         2.00 E -5         27.0                                                        5.00 E -5         59.0                                                        1.00 E -4         81.0                                                        3.15 E -5         80.0                                              LDAH      2.50 E -5         0.0                                               Example 66                                                                    RBL       3.15 E -5         50.0    IC                                        Example 33                                                                    RBL       8.20 E -5         50.0    IC                                        LDAH      2.50 E -5         50.0    IC                                        Example 6                                                                     5LOA      2.00 E -5         50.6    IC                                                  2.10 E -5         50.0    IC                                        Example 67                                                                    RBL       6.56 E -6         50.0    IC                                        Example 67                                                                    RBL       1.04 E -5         50.0    IC                                        5LOA      1.17 E -5         50.0    IC                                        Example 52                                                                    LDAH      6.00 E -5         50.0    IC                                        Example 49                                                                    RBL       1.49 E -4         50.0    IC                                        LDAH      3.50 E -5         50.0    IC                                        Example 50                                                                    LDAH      8.00 E -5         0.0                                               Example 59                                                                    RBL       7.29 E -6         50.0    IC                                        LDAH      2.50 E -5         0.0                                               Example 61                                                                    RBL       2.00 E -5         50.0    IC                                                  2.05 E -5         50.0    IC                                        LDAH      1.00 E -6                 IC                                        Example 9                                                                     LDAH      7.70 E -5         50.0    IC                                        Example 58                                                                    RBL       8.47 E -6         59.0    IC                                        LDAH      8.00 E -5         0.0                                               Example 11                                                                    RBL       3.64 E -6         50.0    IC                                        LDAH      1.10 E -6         50.0    IC                                        Example 4                                                                     LDAH      4.50 E -5         50.0    IC                                        Example 68                                                                    RBL       4.99 E -6         50.0    IC                                        Example 69                                                                    RBL       2.04 E -5         50.0    IC                                        Example 53                                                                    RBL       3.54 E -6         50.0    IC                                        5LOA      3.80 E -6         50.0    IC                                        Example 70                                                                    5LOA      5.00 E -6         50.0    IC                                        Example 71                                                                    RBL       7.46 E -6         50.0    IC                                        LDAH      2.00 E -4         50.0    IC                                         Example 72                                                                   RBL       3.50 E -6         50.0    IC                                        LDAH      2.60 E -6         50.0    IC                                        Example 62                                                                    RBL       1.00 E -5         50.0    IC                                                  5.95 E -6         50.0    IC                                                  4.98 E -6         50.0    IC                                        LDAH      0.00 E 0          0.0                                               Example 73                                                                    RBL       3.84 E -6         50.0    IC                                        5LOA      4.09 E -6         50.0    IC                                                  8.20 E -6         50.0    IC                                        Example 64                                                                    RBL       6.11 E -6         50.0    IC                                                  9.49 E -6         50.0    IC                                                  2.82 E -6         50.0    IC                                        5LOA      1.19 E -5         50.0    IC                                        Example 63                                                                    RBL       4.42 E -6         50.0    IC                                                  3.11 E -6         50.0    IC                                        Example 74                                                                    RBL       5.27 E -6         50.0    IC                                        5LOA      9.30 E -6         50.0    IC                                        Example 75                                                                    RBL       5.58 E -6         50.0    IC                                        Example 76                                                                    RBL       3.00 E -6         50.0    IC                                        5LOA      1.10 E -5         50.0    IC                                        Example 77                                                                    RBL       5.96 E -6         50.0    IC                                        Example 78                                                                    RBL       4.82 E -6         50.0    IC                                        5LOA      1.06 E -5         50.0    IC                                        Example 79                                                                    RBL       5.30 E -7         50.0    IC                                                  4.13 E -7         50.0    IC                                        5LOA      9.20 E -6         50.0    IC                                        Example 80                                                                    RBL       1.27 E -5         50.0    IC                                        5LOA      1.01 E -5         50.0    IC                                        Example 81                                                                    RBL       1.01 E -5         50.0    IC                                        5LOA2     8.40 E -6         50.0    IC                                        Example 8                                                                     RBL       4.21 E -6         50.0    IC                                        5LOA2     5.00 E -6         50.0    IC                                                  4.60 E -6         50.0    IC                                        ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Q is I.sub.2                                                                          Concentration (M)                                                                             % Inhibition                                          ______________________________________                                        Example 83                                                                    5LOA      5.00 E 0          +1.6                                                        2.00 E 0          9.2                                               Example 87                                                                    5LOA       4.00 E -7        50.0    IC                                        LDAH      1.00 E 5          50.0    IC                                        ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Q is I.sub.3                                                                          Concentration (M)                                                                             % Inhibition                                          ______________________________________                                        Example 101                                                                   5LOA       8.50 E -6        56.0    IC                                        LDAH       2.50 E -5        0.0                                               Example 129                                                                   5LOA       5.00 E -7        50.0    IC                                        LDAH       1.60 E -6        50.0    IC                                        Example 117                                                                   LDAH       2.50 E -5        0.0                                               Example 126                                                                   5LOA       3.55 E -6        50.0    IC                                                   2.17 E -6        50.0    IC                                        LDAH       3.20 E -5        50.0    IC                                        Example 121                                                                   5LOA       7.60 E -6        50.0    IC                                        LDAH       1.60 E -6        50.0    IC                                        Example 123                                                                   LDAH       2.50 E -5        50.0    IC                                        Example 124                                                                   5LOA       4.20 E -6        50.0    IC                                        LDAH       6.50 E -6        50.0    IC                                        Example 103                                                                   LDAH       1.10 E -6        50.0    IC                                        Example 122                                                                   5LOA       7.60 E -7        50.0    IC                                        LDAH       2.30 E -6        50.0    IC                                        Example 125                                                                   5LOA       4.01 E -6        50.0    IC                                        LDAH       6.10 E -6        50.0    IC                                        Example 115                                                                   LDAH       8.00 E -5        0.0                                               Example 119                                                                   LDAH       7.90 E -9        50.0                                              Example 113                                                                   5LOA       5.00 E -6        6.3                                                          1.00 E -5        15.3                                                         2.00 E -5        33.7                                              Example 110                                                                   5LOA       6.04 E -6        50.0    IC                                                   6.35 E -6        50.0    IC                                        ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Q is I.sub.4                                                                          Concentration (M)                                                                             % Inhibition                                          ______________________________________                                        Example 131                                                                   RBL        4.40 E -6        50.0    IC                                        LDAH       7.00 E -6        0.0     IC                                        Example 134                                                                   RBL        6.88 E -5        50.0    IC                                        LDAH       8.20 E -6        50.0    IC                                        Example 135                                                                   RBL        1.00 E -4        43.0                                              LDAH       2.50 E -5        50.0    IC                                        Example 136                                                                   RBL        1.00 E -4        11.0                                              5LOA       5.00 E -6        +1.4                                                         2.00 E -5        +2.2                                              Example 137                                                                   RBL1       1.00 E -4        12.0                                              Example 139                                                                   RBL1       1.00 E -4        25.0                                              Example 138                                                                   RBL        1.13 E -4        50.0    IC                                        LDAH       3.30 E -5        50.0    IC                                        Example 142                                                                   RBL        6.10 E -5        50.0    IC                                        5LOA       6.00 E -6        50.0    IC                                        Example 143                                                                   RBL        1.21 E -5        50.0    IC                                        5LOA       5.22 E -6        50.0    IC                                        LDAH       4.40 E -6        50.0    IC                                        Example 144                                                                   RBL        5.00 E -6        50.0    IC                                                   6.43 E -6        50.0    IC                                                   3.28 E -6        50.0    IC                                        5LOA       5.00 E -6        36.0                                                         2.00 E -5        42.5                                              Example 145                                                                   RBL        1.00 E -4        30.0                                              5LOA       1.21 E -5        50.0    X1                                        Example 146                                                                   RBL        1.02 E -6        50.0    IC                                        Example 146                                                                   5LOA       3.96 E -6        50.0    IC                                        Example 147                                                                   RBL        1.00 E -4        3.0                                               5LOA       5.00 E -6        5.5                                                          2.00 E -5        13.8                                              Example 148                                                                   RBL        1.00 E -4        50.0    IC                                        5LOA       5.00 E -6        +7.3                                                         2.00 E -5        19.0                                              ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                        Q is I.sub.5                                                                          Concentration (M)                                                                             % Inhibition                                          ______________________________________                                        Example 150                                                                   5LOA       1.80 E -6        50.0    IC                                        LDAH       4.70 E -6        50.0    IC                                        Example 152                                                                   5LOA       2.00 E -5        38.1                                                         8.00 E -5        79.2                                                         1.00 E -5        23.0                                                         2.00 E -5        33.9                                                         4.00 E -5        76.3                                                         2.31 E -5        0.0                                               LDAH       5.70 E -7        50.0    IC                                        Example 151                                                                   5LOA       1.00 E -5        13.9                                                         4.00 E -5        18.0                                              Example 155                                                                   5LOA       5.00 E -6        +7.6                                                         1.00 E -5        +6.5                                                         2.00 E -5        10.1                                                         1.00 E -5        +5.2                                                         4.00 E -5        2.3                                               ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        Q is I.sub.6                                                                          Concentration (M)                                                                             % Inhibition                                          ______________________________________                                        Example 161                                                                   5LOA       9.00 E -6        50.0    IC                                        Example 158                                                                   5LOA       4.80 E -6        50.0    IC                                        LDAH       0.00 E 0         0.0                                               Example 159                                                                   5LOA       1.18 E -6        50.0    IC                                        Example 163                                                                   5LOA       5.00 E -7        50.0    IC                                        LDAH       2.50 E -5        0.0                                               Example 166                                                                   LDAH       2.70 E -5        50.0    IC                                        ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                        Q is I.sub.7                                                                          Concentration (M)                                                                             % Inhibition                                          ______________________________________                                        Example 175                                                                   5LOA       2.00 E -6        8.0                                                          1.00 E -5        7.0                                                          2.00 E -5        2.0                                               LDAH       2.50 E -5        0.0                                               Example 177                                                                   LDAH       8.00 E -5        50.0    IC                                        ______________________________________                                    

Accordingly, the present invention also includes a pharmaceuticalcomposition for treating one of the above diseases of conditionscomprising an antidisease or anticondition effective amount of acompound of the Formula I as defined above together with apharmaceutically acceptable carrier.

The present invention further includes a method for treating one of theabove named diseases or conditions in mammals, including man, sufferingtherefrom comprising administering to such mammals either orally orparenterally a corresponding pharmaceutical composition containing acompound of Formula I as defined above in appropriate unit dosage form.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets, and suppositories. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders or tablet disintegrating agents; it can also be encapsulatingmaterial. In powders, the carrier is a finely divided solid which is inadmixture with the finely divided active compound. In the tablet theactive compound is mixed with carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from 5 or 10 toabout 70 percent of the active ingredient. Suitable solid carriers aremagnesium carbonate, magnsium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term "preparation" is intended to include the formulation of theactive compound with encapsulating materialas carrier providing acapsule in which the active component (with or without other carriers)is surrounded by carrier, which is thus in association with it.Similarly, cachets are included. Tablets, powders, cachets, and capsulescan be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredientis dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection. Liquid preparations can also be formulated insolution in aqueous polyethylene glycol solution. Aqueous solutionssuitable for oral use can be prepared by dissolving the active componentin water and adding suitable colorants, flavors, stabilizing andthickening agents as desired. Aqueous suspensions suitable for oral usecan be made by dispersing the finely divided active component in waterwith viscous material, i.e., natural or synthetic gums, resins,methylcellulose, sodium carboxymethylcellulose, and other well-knownsuspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroralor parenteral administration. Such liquid forms include solutions,suspensions, and emulsions. These particular solid form preparations aremost conveniently provided in unit dose form and as such are used toprovide a single liquid dosage unit. Alternately, sufficient solid maybe provided so that after conversion to liquid form, multiple individualliquid doses may be obtained by measuring predetermined volumes of theliquid form preparation as with a syringe, teaspoon, or other volumetriccontainer. When multiple liquid doses are so prepared, it is preferredto maintain the unused portion of said liquid doses at low temperature(i.e.,under refrigeration) in order to retard possible decomposition.The solid form preparations intended to be converted to liquid form maycontain, in addition to the active material, flavorants, colorants,stabilizers, buffers, artificial and natural sweeteners, dispersants,thickeners, solubilizing agents, and the like. The liquid utilized forpreparing the liquid form preparation may be water, isotonic water,ethanol, glycerine, propylene glycol, and the like as well as mixturesthereof. Naturally, theliquid utilized will be chosen with regard to theroute of administration, for example, liquid preparations containinglarge amounts of ethanol are not suitable for parenteral use.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriatequantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, for example, packeted tablets, capsules, and powders invials or ampoules.The unit dosage form can also be a capsule, cachet, ortablet itself or it can be the appropriate number of any of these inpackaged form.

The quantity of active compound in a unit dose of preparation may bevariedor adjusted from 1 mg to 500 mg preferably to 1 to 50 mg accordingto the particular applicatio and the potency of the active ingredient.The compositions can, if desired, also contain other compatibletherapeutic agents.

In therapeutic use as described above, the dosages may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe art. Generally, treatment is initiated with smaller dosages whichare less thanthe optimum dose of the compound. Thereafter the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired. ##STR1##

We claim:
 1. A compound having the formula (I)and pharmaceuticallyacceptable salts thereof, wherein (1) y is one or two; (2) Q is asubstituent selected from the group consisting of the formula ##STR2##wherein b is zero, one, two, three, or four, X is independently hydrogenor lower alkyl; R₁ may be the same or different if b is two or more,selected from a group consisting of alkyl of from one to four carbons,inclusive; alkoxy of from one to four carbons, inclusive; carboalkoxy offrom two to four carbons, inclusive; hydroxy, halogen, nitro, amino,mono- and di- alkylamino having each alkyl the same or different fromone to four carbons inclusive; carbalkoxy amido, of from one to fourcarbons, inclusive; alkylsulfonamido of from one to four carbons,inclusive; alkylsulfinyl of from one to four carbons, inclusive;alkylsulfonyl of from one to four carbons, inclusive; and--(CH═CH--CH═CH)-- taken together with an adjacent ring carbon to form abenzo radical; (3) R₅ is hydrogen, alkyl of from one to four carbons,inclusive; carbalkoxy of from two to four carbons, inclusive; hydroxy,halogen; or --CH═CH--CH═CH-- taken together with adjacent carbons toform a benzo radical; (4) R₆ is alkyl of from six to twenty carbons,--CH═CH--R₄, -- inclusive, nitro, alkanesulfonamido of from one to fourcarbons, phenyl.
 2. A compound according to claim 1 and being2-Benzofurancarboxamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-2,3-dihydro-7-methoxy-3-oxo-.3. A compound according to claim 1 and beingNaphtho[2,3-b]furan-2-carboxamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-2,3-dihydroxy-3-oxo-.
 4. Acompound according to claim 1 and being 2-Benzofurancarboxamide,N-[4-[2-(3,4-dimethoxyphenyl)ethylphenyl)-3-hydroxy-.
 5. A compoundaccording to claim 1 and being Naphtho[2,1-b]furan-2-carboxamide,1-hydroxy-N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl].
 6. A compoundaccording to claim 1 and being Naphtho[2,3-b]furan-2-carboxamide,N-(4-dodecylphenyl)-3-hydroxy-.
 7. A compound according to claim 1 andbeing 2-Benzofurancarboxamide, N-(4-dodecylphenyl)-3-hydroxy-.
 8. Acompound according to claim 1 and beingNaphtho[1,2-b]furan-2-carboxamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-2,3-dihydro-3-oxo-.
 9. Acompound according to claim 1 and being 2-Benzofurancarboxamide,n-(4-decylphenyl)-3-hydroxy-.
 10. A compound according to claim 1 andbeing Naptho[2,1-b]furan-2-carboxamide, N-(4-decylphenyl)-3-hydroxy. 11.A compound according to claim 1 and beingNaptho[2,1-b]furan-2-carboxamide,N-[4,2-(3,4-dimethylphenyl)ethyl]phenyl]-1-hydroxy-.
 12. A compoundaccording to claim 1 and being Naphtho[2,1-b]furan-2-carboxamide,N-[4-[2-(4-hydroxy-3-methoxyphenyl)ethyl]phenyl]-1,2-dihydro-1-oxo-. 13.A compound according to claim 1 and being 2-Benzofuranacetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-2,3-dihydro-7-methoxy-α,3-dioxo-.14. A compound according to claim 1 and beingNaphtho[2,1-b]furan-2-acetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-1-hydroxy-α-oxo-.
 15. Acompound according to claim 1 and being Naphtho[1,2-b]furan-2-acetamide,N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl]-3-hydroxy-α-oxo-.
 16. Acompound according to claim 1 and being Naphtho[1,2-b]furan-2-acetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-α-oxo-.
 17. Acompound according to claim 1 and being 2-Benzofuranacetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-5,6-dimethoxy-α-oxo-.18. A compound according to claim 1 and being 2-Benzofuranacetamide,N-(4-decylphenyl)-2,3-dihydro-α,3-dioxo-.
 19. A compound according toclaim 1 and being Naptho[2,3-b]furan-2-acetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-2,3-dihydro-α,3-dioxo-.
 20. Acompound according to claim 1 and being 2-Benzofuranacetamide,N-[4-[2-(3,4-dichlorophenyl)ethyl]phenyl-2,3-dihydro-α,3-dioxo-.
 21. Acompound according to claim 1 and being 2-Benzofuranacetamide,N-[4-decylphenyl]-3-hydroxy-5,6-dimethoxy-α-oxo-.
 22. A compoundaccording to claim 1 and being Naphtho[2,3-b]furan-2-acetamide,N-[4-decylphenyl]-2,3-dihydro-α,3-dioxo-.
 23. A compound according toclaim 1 and being 2-Benzofuranacetamide,N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-3-hydroxy-α-oxo-.
 24. Acompound according to claim 1 and beingNaphtho[2,1-b]furan-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-1-hydroxy-.
 25. A compoundaccording to claim 1 and being 2-Benzofurancarboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-7-methoxy-α-oxo 26.A compound according to claim 1 and being 2-Benzofurancarboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-.
 27. A compoundaccording to claim 1 and being Naphtho[1,2-b]furan-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-.
 28. A compoundaccording to claim 1 and being 2-Benzofuranacetamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-2,3-dihydro-α,3-dioxo-.
 29. Acompound according to claim 1 and being 2-Benzofuranacetamide,N-(4-decylphenyl)-3,5,6-trihydroxy-α-oxo-.
 30. A compound according toclaim 1 and being Naphtho[2,3-b]furan-2-carboxamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3-hydroxy-.
 31. A compoundaccording to claim 1 and being Naphtho[2,3-b]furan-2-acetamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]2,3-dihydro-α,3-dioxo-.
 32. Acompound according to claim 1 and being 2-Benzofuranacetamide,N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-3,5,6-trihydroxy-α-oxo-. 33.A pharmaceutical composition comprising an antiasthmatic, antiallergic,cardiovascular, antimigraine or antiinflammatory effective amount of acompound as claimed in claim 1 together with a pharmaceuticallyacceptable carrier.
 34. A method for treating asthma, allergy,cardiovascular disease, migraine or inflammation in a mammal sufferingtherefrom, which comprises administering to said mammal a compound inclaim 1.